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Biochemistry > Module 3 > Flashcards

Module 3 Flashcards

1
Q

Functions: Plasma Membrane

A
  • Endocytosis (“Cleanup”)
  • Communication With Other Cells/Tissues
  • Anchor Cytoskeleton
  • Entry/Exit of Cellular Materials
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2
Q

Liposome

A

A spherical vesicle bounded by a lipid bilayer that contains an aqueous central environment.

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3
Q

Relationship: Saturation vs. Fluidity

Plasma Membranes

A
  • The higher the saturation of a plasma membrane, the less fluidity it possesses.
  • The higher the unsaturation of a plasma membrane, the greater fluidity it possesses.
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4
Q

Cholesterol

A

A small amphipathic molecule composed of a rigid nonpolar ring system connected to a hydroxyl group that is a frequent component of biological membranes.

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5
Q

Effect of Cholesterol on Membrane Fluidity

A
  • Low Amount of Cholesterol: Cholesterol increases membrane fluidity by preventing saturated hydrocarbon chains from close-packing.
  • High Amount of Cholesterol: Cholesterol decreases membrane fluidity due to its rigid nonpolar ring structure.
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6
Q

Effect of Cholesterol on Membrane Thickness

A
  • High Proportion of Cholesterol: The plasma membrane thickens due to the high number of rigid cholesterol rings between the phospholipids.
  • Low Proportion of Cholesterol: The plasma membrane thins out due to the low number of cholesterol ring structures between the phospholipids.
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7
Q

In what ways are phospholipid molecules able to move within a plasma membane?

A
  • Laterally
  • Rotationally
  • Transversely
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8
Q

Flippase

A

A membrane protein that uses energy from ATP hydrolysis to catalyze the outside-to-inside “flipping” of membrane phospholipids.

Flippase is a P-Type ATPase protein.

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9
Q

Floppase

A

A membrane protein that uses energy from ATP hydrolysis to catalyze the inside-to-outside “flopping” of membrane phospholipids.

Floppase is an ABC Transporter protein.

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10
Q

Scramblase

A

A membrane protein that uses energy from ATP hydrolysis to catalyze bidirectional transverse movement of membrane phospholipids to achieve equilibrium.

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11
Q

What are the driving forces of spontaneous lipid bilayer assembly?

A
  • Hydrophobic Interactions (Entropic Forces)
  • Van Der Waals Forces (Packing of Hydrocarbon Chains)
  • Electrostatic Interactions + Hydrogen Bonding
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12
Q

Endomembrane System

A

The intracellular network of plasma membranes that is used to transport materials throughout the cytoplasm via vesicles.

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13
Q

Glycerophospholipid

A

A membrane lipid composed of two fatty acid chains, a glycerol molecule, a phosphate group, and a polar head group.

Glycerophospholipids are the most abundant type of eukaryotic membrane lipids.

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14
Q

Sphingolipid

A

A membrane lipid composed of a sphingosine molecule bound to a single fatty acid chain and a polar head region.

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15
Q

Three Major Types of Membrane Lipids

A
  • Glycerophospholipids
  • Sphingolipids
  • Cholesterol
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16
Q

Types of Glycerophospholipids

Eukaryotes

A
  • Phosphatidylcholine
  • Phosphatidylethanolamine
  • Phosphotidylserine
  • Phosphotidylinositol
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17
Q

Types of Sphingolipids

A
  • Sphingophospholipids
  • Sphingoglycolipids
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18
Q

Sphingophospholipid

A

A type of sphingolipid containining one sphingosine chain, one fatty acid chain, and a (polar head group)-linked phosphate group.

Ex: Sphingomyelin

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19
Q

Types of Sphingoglycolipids

A
  • Cerebrosides: Contain a glucose/galactose bound to the terminal —OH group.
  • Gangliosides: Contain an oligosaccharide/polysaccharide bound to the terminal —OH group.
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20
Q

Sphingoglycolipid

A

A types of sphingolipid containining one sphingosine chain, one fatty acid chain, and a saccharide glycan moiety.

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21
Q

What proportion of plasma membrane lipids are cholesterol?

A

25%–40%

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22
Q

What is the lipid and protein compositions of most plasma membranes?

A
  • Protein: ~50%
  • Lipid: ~50%
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23
Q

Fluid Mosaic Model

A

A model of cell membrane organization proposing that the membrane is a two-dimensional solution in which membrane proteins can freely move laterally and transversely through the bilayer.

It has since been shown that the Fluid Mosaic Model is an overly simplistic view of eukaryotic cell membrane organization.

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24
Q

Phosphatidate

A

The simplest type of glycerophospholipid that consists of a glycerol linked to two fatty acid chains and a (polar head group)-linked phosphate group.

Phosphatidate serves as the precursor for many of the common types of glycerophospholipids.

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25
Q

Phospholipases

A

Enzymes that cleave glycerophospholipid fatty acid chains by catalyzing hydrolytic reactions.

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26
Q

Sphingosine

A

A long-chain amino alcohol synthesize from palmitate and serine.

Sphingolipids are derived from sphingosine.

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27
Q

Ceramide

A

A sphingosine molecule covalently linked to a fatty acid chain that serves as the precursor for sphingophospholipids and sphingoglycolipids.

  • Sphingophospholipid: Phosphocholine + Ceramide
  • Cerebroside: Monoglycosylated Ceramide
  • Ganglioside: Oligoglycosylated Ceramide
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28
Q

Which type of membrane lipid is distributed equally across the inner/outer membrane monolayers?

A

Cholesterol

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29
Q

What type(s) of membrane proteins are involved in active transport processes?

A

Carrier Proteins

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30
Q

What type(s) of membrane proteins are involved in passive transport processes?

A
  • Channel Proteins
  • Carrier Proteins
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31
Q

Rate: Channel Proteins vs. Carrier Proteins

A
  • Channel Proteins: Slower than Diffusion
  • Carrier Proteins: Comparable to Diffusion
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32
Q

Selectivity: Channel Proteins vs. Carrier Proteins

A
  • Channel Proteins: Semiselective
  • Carrier Proteins: Highly Selective
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33
Q

Which type of membrane transport protein can become saturated?

A

Carrier proteins can become saturated at high substrate/ligand concentrations (due to their slow rate of biomolecule translocation).

Channel proteins do NOT usually become saturated with substrate, so their rate of biomolecule translocation increases with increasing [substrate].

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34
Q

Equation: Free Energy Change of Membrane Transport

A

  • R: Gas Constant
  • T: Temperature
  • C2: End-Point Concentration
  • C1: Start-Point Concentration
  • Z: Charge of Solute Molecule
  • F: Faraday Constant
  • V: Membrane Potential
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35
Q

Sarcoplasmic Reticulum

A

An organelle within muscle fibers used to store Ca2+ ions that will be released during muscular contraction.

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36
Q

Porin

A

A passive membrane transport channel protein that possesses a β-barrel structural motif and is organized as a homotrimer.

  • Porins are abundant in the outer membranes of bacteria, mitochondria, and chloroplasts.
  • Porins are permeable to ions and small molecules.
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37
Q

Structure: Porins

A
  • Nonpolar amino acid residues face outward toward the hydrophobic region of the cell membrane.
  • Polar/charged amino acid residues face inward and interact with the polar/charged molecules being transported.
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38
Q

Selectivity: Porins

A

Porins can be either relatively nonselective or highly selective (depending on the inner diameter of the channel and the chemical properties of the channel’s amino acid side chains).

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39
Q

Non-Selective Porins

A

Nonspecific porin molecules that allow for molecular passage solely according to the size of the transported molecule.

The inner diameter size of non-selective porins is determined by the number of β-strands the channel consists of.

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40
Q

Selective Porins

A

Highly specific porin molecules that permit molecular passage based on the chemical characteristics of the transported molecule.

The chemical proporties of the porin’s inner-facing hydrophilic amino acid side chains determine the channel’s specificity for particular molecules.

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41
Q

Selectivity Channel

A

A narrow opening within the interior of a channel protein complex that allows only certain ions to pass through the membrane in different conditions.

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42
Q

How does the selectivity channel of the K+ Channel Protein distinguish between K+ ions and Na+ ions?

A

The carbonyl Oxygen atoms within the selectivity channel are positioned such that they provide a favorable desolvation energy for K+ ions (and not for Na+ ions).

Na+ ions do NOT pass through the selectivity channel because their slightly smaller ionic radii cause the transition between Na+-H2O interactions and Na+-Oxygencarbonyl interactions to be unfavorable.

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43
Q

Aquaporin

A

Passive membrane transport protein responsible for transporting water molecules across the cell membrane.

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44
Q

Structure: Aquaporins

A
  • Each aquaporin monomer is comprised of 6 transmembrane α-helices.
  • An aquaporin protein complex is tetrameric (i.e. consists of 4 monomers).
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45
Q

What determines the selectivity of aquaporin proteins?

A

Two short α-helices protrude into the aquaporin’s channel to create a constriction point that narrows the channel opening such that only a single H2O molecule can pass through.

The Asn residues at the α-helix N-terminals aid in the aquaporin’s selectivity by forming hydrogen bonds with H2O molecules.

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46
Q

Primary Active Transporter

A

An active transport protein that uses the hydrolysis of ATP to drive molecules across membranes against their concentration gradient.

Primary active transporters typically undergo significant conformational changes (powered by ATP hydrolysis) to transport molecules across membranes.

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47
Q

Main Types of Primary Active Transporters

A
  • P-Type (Phosphorylated-Type) Transporters
  • ATP-Binding Cassette (ABC) Transporters
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48
Q

P-Type Transporter

A

A primary active membrane transport protein that hydrolyzes ATP and become phosphorylated to drive large conformational changes and pump molecules across the membrane.

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49
Q

ABC Transporters

ATP-Binding Cassette Transporters

A

A primary active membrane transport protein that hydrolyzes ATP (without becoming become phosphorylated) to drive large conformational changes and pump molecules across the membrane.

ABC Transporter conformational changes include the conversion from an outward-facing transporter to an inward-facing transporter.

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50
Q

Secondary Active Transporter

A

An active transport protein that drives molecules across membranes against their concentration gradient by using energy from the co-transport of another molecule down its concentration gradient.

The co-transport mechanism (of a secondary active transporter) is typically coupled to an ATP-dependent primary active transport mechanism to establish a concentration gradient.

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51
Q

Antiporter

A

A secondary active membrane transport proteins that moves molecules across a membrane in opposite directions.

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52
Q

Symporter

A

A secondary active membrane transport proteins that moves molecules across a membrane in the same direction.

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53
Q

H+–K+ ATPase

A

A P-type primary active transporter responsible for pumping H+ ions into the stomach to lower the pH of gastric juices.

The H+–K+ ATPase uses energy from ATP hydrolysis to exchange H+ ions and K+ ions across the cell membrane.

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54
Q

Na+–K+ ATPase

A

A P-type primary active transporter responsible for maintaining a Na+ ion gradient across cell membranes.

  • The Na+–K+ ATPase uses phosphoryl transfer energy from ATP hydrolysis to drive large protein confirmational changes that facilitate ion transport.
  • The Na+–K+ ATPase exports 3 Na+ ions and imports 2 K+ ions.
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55
Q

Structural Domains: Na+–K+ ATPase

A
  • M: Transmembrane Domain
  • A: Regulatory Domain
  • P: Phosphoryl Domain
  • N: ATP-Binding Domain
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56
Q

Structural Domains: SERCA

A
  • M: Transmembrane Domain
  • A: Regulatory Domain
  • P: Phosphoryl Domain
  • N: ATP-Binding Domain

SERCA transporters and Na+–K+ ATPases consist of the same general domain structures.

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57
Q

Sarco/Endoplasmic Reticulum Ca2+–ATPase

SERCA

A

A P-type primary active transporter responsible for transporting Ca2+ ions from the sarcoplasm to the sarcoplasmic reticulum to promote muscle relaxation.

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58
Q

Mechanism: SERCA

A
  1. Phosphorylation of Phospholamban by PKA and CaMKII causes its dissociation from SERCA.
  2. Dissocation leads to a SERCA conformational change that allows it to uptake/bind Ca2+ from the sarcoplasm.
  3. ATP hydrolysis (and subsequent dissocation of ADP) by SERCA opens up a lumen-side channel that enables the **release of Ca2+ into the SR**.

ATP-binding to SERCA (and subsequent release of inorganic phosphate) returns the protein channel to its resting-state conformation in complex with Phospholamban.

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59
Q

Detailed Mechanism: Ca2+ Transport via SERCA

A
  1. E2-ATP releases 2 H+ ions into the sarcoplasm
  2. E2-ATP traps 2 Ca2+ ions within its M-Domain (betweent the M2 and M3 subdomains) binding pocket.
  3. Asp351 is phosphoylated (resulting form ATP hydrolysis) to generate Ca2+-E1-P-ADP.
  4. ADP dissociates from Ca2+-E1-ADP to generate E2P.
  5. M2 moves away from M3 to create an opening toward the SR lumen that allows Ca2+ to exit E2P’s M-Domain binding pocket.
  6. 2 H+ ions enter E2P’s M-Domain binding pocket.
  7. ATP binds to E2P’s N-Domain to generate E2P-ATP.
  8. Asp351 is dephosphorylated to regenerate E2-ATP and create an opening into the sarcoplasm.
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60
Q

4 Conformations: SERCA-Facilitated Ca2+ Transport

A
  1. E2-ATP
  2. Ca2+-E1-P-ADP
  3. E2P
  4. E2P-ATP
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61
Q

4 Steps: SERCA-Facilitated Ca2+ Transport

A
  1. When in the E2-ATP conformation, SERCA releases 2 H+ ions into the sarcoplasm and traps 2 Ca2+ ions within its M-Domain binding pocket. Phosphorylation of Asp351 via ATP hydrolysis converts E2-ATP to the Ca2+-E1-P-ADP conformation.
  2. ADP dissociates from SERCA to convert Ca2+-E1-P-ADP conformation to the E2P conformation. The M2 Subdomain separates from the M3 Subdomain to create an SR-side opening that enables Ca2+ to leave the M-Domain binding pocket.
  3. 2 H+ ions bind to SERCA’s M-Domain binding pocket. ATP binds to SERCA to convert E2P to the E2P-ATP conformation. The M2 Subdomain rejoins with M3 to seal the binding pocket.
  4. Asp351 is dephosphorylated to convert E2P-ATP to the E2-ATP conformation, which possesses an opening toward the sarcoplasm.
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62
Q

Permeability Glycoprotein (P-Glycoprotein) Transporter

Multidrug Resistance Protein

A

An ABC export transport protein responsible for removing toxic compounds from the cell.

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63
Q

Why is the Multidrug Resistance Protein problematic in for cancer treatment?

A

Cancer cells can become resistant to chemotherapy drugs by increasing the number of Multidrug Resistance Proteins (MRPs) in the cell membrane.

The high quantity of MRPs causes the removal the chemotherapy drug(s) from the cell become they can become effective.

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64
Q

Examples: ABC Transport Proteins

A
  • P-Glycoprotein Transporter
  • CFTR Protein
  • A. Fulgidus Molybdate Transporter
  • E. Coli Maltose Transporter
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65
Q

Aftermath of ATP Hydrolysis: ABC Transporters vs. P-Type Transporters

A
  • P-Type Transporters form a phosphorylated intermediate from minor conformational changes.
  • ABC Transporters experience large conformational changes that convert the transporter from outward-facing to inward-facing.
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66
Q

Formation of ATP Catalytic Sites: ABC Transporters vs. P-Type Transporters

A
  • P-Type Transporters do NOT require initial conformational changes to generate the ATP catalytic site.
  • ABC Transporters requires an initial conformational change that brings 2 ATP-binding half-sites together to generate the ATP catalytic site.
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67
Q

Structural Domains: ABC Transporters

A
  • Periplasmic Side (of Transmembrane Domain)
  • Transmembrane Domain
  • Nucleotide-Binding Domain

  • The periplasmic side (of the transmembrane domain) contains binding sites for periplasmic substrate carrier proteins.
  • The nucleotide-binding domains serve as the ATP catalytic sites.
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68
Q

Mechanism: Metabolite Import via ABC Transporters

A
  1. A periplasmic substrate carrier protein binds to the periplasmic side of the ABC Transporter transmembrane domain.
  2. The ABC Transporter undergoes a conformational change that exposes an internal substrate-binding site (that the substrate enters) and brings the nucleotide-binding domains together (to form 2 ATP-binding sites).
  3. The ABC Transporter hydrolyzes ATP to cause another conformational change that opens the substrate-binding site to the cytoplasm (for the substrate to exit).
  4. ATP replaces ADP + Pi within the nucleotide-binding domains to regenerate the ABC Transporter resting state.
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69
Q

3 Steps: Metabolite Import via ABC Transporters

A
  1. Binding of the periplasmic substrate carrier protein to the ABC Tranporter’s periplasmic side induces a conformational change that exposes the substrate binding site to the periplasm (and allows substrate entry into the ABC Transporter).
  2. ATP hydrolysis causes another conformational change that exposes the substrate binding site to the cytoplasm (and allows substrate ejection from the ABC Transporter).
  3. Release of ADP + Pi from the ABC Transporter and subsequent binding of ATP to the ABC Transporter regenerates the resting state conformation.
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70
Q

Why is it critical that ABC Transporters’ substrate-binding sites are accessible to only one side at a time?

A

ABC Transporters move substrates across the membrane against their concentration gradients, so substrate access must only be possible on the side of low [substrate].

By closing off the substrate-binding pocket to the perisplasmic space (following ATP hydrolysis), the ABC Transporter ensures that the substrate exits into cytoplasm (and prevents substrate equilibration).

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71
Q

How does Secondary Active Transport indirectly use energy generated by ATP hydrolysis?

A

Secondary Active Transporters use the potential energy stored in concentration gradients that were generated by ATP hydrolysis (or redox energy).

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72
Q

Examples: Secondary Active Transporters

A
  • Lactose Permease Symporter
  • Na+–I– Symporter
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73
Q

Na+–I– Symporter

A

A secondary active transport protein in thyroid gland cells that imports Iodide (I–) ions into cells for thyroid hormone synthesis.

The Na+–I– Symporter imports one I– ion into the cell for every two Na+ imported.

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74
Q

What generates the Na+ gradient across thyroid gland cell membranes that is used by the Na+–I– Symporter to import I–?

A

Na+–K+ ATPase (Primary Active Transporter)

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75
Q

Receptor Protein

A

A protein that stimulates a cellular repsonse after the binding of a ligand initiates protein structural changes.

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76
Q

Signal Transduction

A

The biochemical mechanism responsible for transmitting extracellular signals across the plasma membrane and throughout the cell.

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77
Q

Target Protein

A

An intracellular protein that is modified (either covalantly of noncovalently) as a result of an upstream signal transduction pathway.

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78
Q

Cell Signaling Pathway

A

A linked set of biochemical reactions that are initiated by ligand-induced receptor protein activation and terminated by measurable cellular responses.

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79
Q

First Messenger

A

An extracellular ligand that binds to a receptor protein to activate a cell signaling pathway.

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80
Q

Second Messenger

A

A nonprotein intracellular molecule that transmits, amplifies, and terminates a biochemical signal (via its functional linkage with a signaling protein).

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81
Q

Signaling Protein

A

A protein that transmits a biochemical signal from a receptor protein to a second messenger or from a second messenger to a target protein.

  • Upstream signaling proteins transmit biochemical signals from receptor proteins to second messengers.
  • Downstream signaling proteins transmit biochemical signals from second messengers to target proteins.
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82
Q

Insulin

A

A peptide hormone secreted by pancreatic β cells that regulates blood glucose levels by binding to the insulin receptor and activating pathways that remove glucose from the blood.

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83
Q

Hormone

A

A biologically active compound released into the circulatory system that binds to hormone receptors within/on target cells.

Hormones are a type of first messenger.

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84
Q

Why are hormones considered a type of first messenger in cell signaling pathways?

A

Hormones initiate the receptor-activating signal (of a cell signaling pathway) that gives rise to a physiological response.

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85
Q

Examples: First Messengers

A
  • Acetylchloine
  • Cortisol
  • Epidermal Growth Factor (EGF)
  • Epinephrine/Adrenaline
  • Glucagon
  • Insulin
  • Testosterone
  • Prostaglandins
  • β-Estradiol/Estrogen
  • Ca2+
  • CO2
  • NO (Nitric Oxide)
  • Amino Acids
  • Nucleotides
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86
Q

Nitric Oxide

NO

A

A first messenger molecule that rapidly diffuses into smooth muscle cells to cause muscle relaxation, vasodilation, and increased blood flow.

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87
Q

How is Nitric Oxide synthesized via Nitric Oxide Synthase?

A

Nitric Oxide is synthesized as a byproduct of the Arginine-to-Citrulline reaction catalyzed by NO Synthase.

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88
Q

Cyclic GMP

cGMP

A

A nucleic acid produced from GTP (via Guanylate Cyclase) that serves as the second messenger for numerous signaling pathways.

89
Q

How does NO contribute to the synthesis of cGMP?

A

The binding of NO to Guanylyl Cyclase activates the receptor enzyme (to allow it to convert GTP to cGMP).

90
Q

cGMP Phosphodiesterase

A

A catalytic enzyme that hydrolyzes cGMP.

91
Q

Cyclic AMP

cAMP

A

A nucleic acid produced from ATP (via Adenylate Cyclase) that serves as a second messenger to activate numerous signaling proteins and target proteins.

92
Q

Guanylate Cyclase

Guanylyl Cyclase

A

A membrane-bound enzymatic receptor that produces cGMP from GTP.

The intracellular Guanylyl Cyclase domain serves as the catalying/cGMP-forming region.

93
Q

Adenylate Cyclase

Adenylyl Cyclase

A

A membrane-bound enzymatic receptor that produces cAMP from ATP.

The intracellular Auanylyl Cyclase domain serves as the catalying/cGMP-forming region.

94
Q

cAMP Phosphodiesterase

A

A catalytic enzyme that hydrolyzes cAMP (to produce AMP).

95
Q

Examples: Second Messengers

A
  • cGMP
  • cAMP
  • DAG
  • IP3
  • Ca2+
96
Q

Diacylglycerol

DAG

A

A second messenger signaling lipid produced by PLC that binds to and activates Protein Kinase C.

97
Q

Inositol-1,4,5-Triphosphate

IP3

A

A second messenger molecule produced by PLC that activates Ca2+ channels on the endoplasmic reticulum (to rapidly increase cytoplasmic Ca2+ levels).

98
Q

Phospholipase C

PLC

A

A membrane-associated enzyme responsible for controlling the intracellular levels of DAG and IP3.

Phospholipase C hydrolyzes PIP2 to form DAG and IP3.

99
Q

Phosphatidylinositol Biphosphate

PIP2

A

A membrane phospholipid that is hydrolyzed (by PLC) to produce DAG and IP3.

100
Q

Protein Kinase C

PKC

A

A kinase protein that phosphorylates downstream target molecules (of a cell signaling pathway) after being activated by DAG.

Protein Kinase C can be activated via binding of 2 Ca2+ ions.

101
Q

Cadmodulin

A

A signaling protein that binds to and activates numerous target proteins (while undergoing a large conformational change) after binding 4 Ca2+ ions.

102
Q

Which second messenger regulates the activities of both PKC and Cadmodulin?

A

Ca2+

103
Q

Signal Amplification

A

The process by which a signal initiated at the cell surface leads to multiple/numerous downstream events through the actions of enzyme-mediated catalyzed reactions.

104
Q

Five Classes of Receptor Proteins

Higher Eukaryotes

A
  • G Protein-Coupled Receptors
  • Receptor Tyrosine Kinases
  • Tumor Necrosis Factor Receptors
  • Nuclear Receptors
  • Ligand-Gated Ion Channels
105
Q

G Protein-Coupled Receptor

GPCR

A

A receptor protein that (upon activation) causes the dissocation of the heterotrimeric G Protein complex, which leads to the activation of downstream enzymes/signaling.

106
Q

Receptor Tyrosine Kinase

RTK

A

A receptor protein containing an extracellular domain that binds ligands and an intracellular domain that phosphorylates tyrosine residues in target proteins (to initiate downstream signaling pathways).

Receptor Tyrosine Kinases signal through adaptor proteins that bind phosphotyrosine residues on the receptor’s intracellular domain.

107
Q

Tumor Necrosis Factor Receptor

TNF Receptor

A

A membrane receptor protein that forms receptor trimers to activate signaling pathways controlling inflammation and apoptosis.

108
Q

Nuclear Receptor

A

A transcription factor receptor protein that regulates gene expression in response to ligand binding.

109
Q

Ligand-Gated Ion Channel

A

A receptor protein that controls the flow of ions across cell membranes in response to ligand binding

110
Q

Examples: Nuclear Receptors

A
  • Glucocorticoid Receptor
  • Vitamin D Receptor
111
Q

Nicotinic Acetylcholine Receptor

A

A ligand-gated ion channel that mediates transmembrane ion transport in response to the Acetylcholine neurotransmitter.

112
Q

Role of Nicotinic ACh Receptors in Neuromuscular Junctions

A

The binding of Acetylcholine to Nicotinic ACh receptors (at the receptor’s α subunit) on the muscle fiber’s plasma membrane induces a conformational change that opens the ion channel and allows entry of K+ and Na+ into the muscle cell.

113
Q

Structure: GPCR

A
  • GPCRs are composed of 7 transmembrane (7TM) α-helices.
  • The GPCR N-terminus is oriented toward the extracellular space; the GPCR C-terminus is exposed to the cytosolic side.
114
Q

Gα Subunit

Gα

A

A G Protein subunit possessing an intrinsic GTPase ability that deactivates downstream signaling mechanisms.

115
Q

Rhodopsin

A

A GPCR consisting of 7 transmembrane α-helices and a bound retinal molecules that absorbs light.

Rhodopsin transduces light signals (sensed by the retinal light sensor) to cytosolic signaling proteins through receptor-mediated conformational changes.

116
Q

Heterotrimeric G Protein

Gαβγ

A

A membrane-bound protein complex associated with a GPCR that dissociates (upon ligand binding to the GPCR) to initiate downstream signaling pathways.

The heterotrimeric G protein consists of one Gα subunit, one Gβ subunit, and one Gγ subunit.

117
Q

Active vs. Inactive: G-Protein States

A
  • Active: The Gα is bound to GTP.
  • Inactive: The Gα is bound to GDP.
118
Q

What causes Gα dissociation from the heterotrimeric G Protein complex?

A

The exchange of GDP for GTP within the Gα subunit activates Gα such that it dissociates from the heterotrimeric complex.

119
Q

Transducin

A

The inactive state of the heterotrimic G Protein complex in which the Gα subunit is bound to GDP.

120
Q

3 Steps: GPCR Signaling

A
  1. Ligand binding to the GPCR activates the receptor and induces conformational changes in the receptor’s cytoplasmic side. The activated GPCR binds an inactivated heterotrimeric G Protein complex.
  2. The activated GPCR promotes exchange of GDP for GTP within the Gα subunit, which leads to G Protein dissociation into Gα-GTP and Gβγ.
  3. Gα-GTP and Gβγ stimulate/regulate downstream signaling processes.
121
Q

Glucagon

A

A peptide hormone relased by the pancreas in response to low blood glucose levels to stimulate glycogen degredation and gluconeogenesis pathways in liver cells.

122
Q

Catecholamines

A

A class of first messenger hormones that are derived from tyrosine.

123
Q

Examples: Catecholamines

A
  • Epinephrine/Adrenaline
  • Norepinephrine/Noradrenaline
  • Dopamine
124
Q

Receptor Agonist

A

A compound that binds to and activates a receptor protein in a similar way as the natural ligand for the receptor.

125
Q

Receptor Antagonist

A

A compound that binds to and deactivates/blocks a receptor protein by preventing the binding of the natural receptor.

The binding of the receptor antagonist (to the receptor) prevents structural changes form occurring within the receptor that would initiate signal transduction mechanisms.

126
Q

What facilitates the binding of the Gsα subunit to Adenylate Cyclase?

A

The exchange of GDP for GTP within the Gsα subunit induces a Gsα conformational change that allows it to bind Adenylate Cyclase.

The Switch II Helix region of Gsα (originally bound to the inactive Gβγ complex) undergoes a conformational change in the presence of bound GTP such that Gsα is able to interact with Adenylate Cyclase.

127
Q

What is the primary response to elevated intracellular cAMP levels?

Liver Cells

A

Activation of Protein Kinase A

128
Q

Protein Kinase A

PKA

A

A signaling protein that activates numerous target proteins/enzymes in the cAMP signaling pathway via phosphorylation.

129
Q

Structure: Protein Kinase A

A

R2C2 Tetramer (2 Regulatory Subunits + 2 Catalytic Subunits)

Activation of PKA occurs when 2 cAMP molecules bind to each regulatory subunit to release the active catalytic subunits.

130
Q

Downstream Metabolic Responses of Gsα Signaling

Glucagon/β2-Adrenergic Receptor Activation

A
  • Phosphorylation/Inhbition of Glycogen Synthase
  • Phosphorylation/Activation of Glycogen Degredation Enzymes
  • Phosphorylation/Activation of Gluconeogensis Enzymes
131
Q

Downstream Metabolic Responses of Gqα Signaling

α1-Adrenergic Receptor Activation

A
  • Phosphorylation/Inhbition of Glycogen Synthase
  • Phosphorylation/Activation of Glycogen Degredation Enzymes
132
Q

What effect does Rac/Gqα binding have on Phospholipase C?

A

The binding of Rac/Gqα (when in the GTP-bound state) to PLC’s Pleckstrin Homology domain stabilizes PLC at the plasma membrane and optimally orients PLC for PIP2 binding.

133
Q

Guanine Nucleotide Exchange Factor

GEF

A

A protein that promotes GDP-to-GTP exchange within the Gα subunit to activate downstream signaling mechanisms.

The activity of Guanine Nucleotide Exchange Factors is countered by GTPase Activating Proteins.

134
Q

GTPase Activating Protein

GAP

A

A protein that stimulates the intrisinic GTP-hydrolyzing activity of Gα proteins to inhibit downstream signaling mechanisms.

The activity of GTPase Activating Proteins is countered by Guanine Nucleotide Exchange Factors.

135
Q

Regulator of G Protein Signaling

RGS

A

A GAP that functions with Gα Proteins associated with GPCRs.

136
Q

G Protein Cycle

A

The sequential stimulation of G Protein signaling (by GEF proteins) and subsequent activation of its intrisic GTPase activity (by GAPs).

137
Q

How does Gα terminate the G Protein signaling pathway?

A

The hydrolysis of GTP (stimulated by a GAP) via the intrinsic GTPase activity of Gα converts GTP to GDP within the Gα active site.

138
Q

How can a GPCR-mediated signal be terminated?

A
  • Gα-Mediated GTP Hydrolysis
  • GPCR Desensitization via GRKs
  • Feedback Inhibition via PKA Phosphorylation
139
Q

G Protein-Coupled Receptor Kinase

GRK

A

A regulatory kinase protein that phosphorylates the GPCR cytoplasmic domain (on Serine or Threonine residues) to mark the receptor for cellular recycling.

140
Q

β-Adrenergic Receptor Kinase

βARK

A

A type of GRK that phosphorylates the β2-Adrenergic Receptor cytoplasmic domain (on Serine or Threonine residues) to terminate the receptor’s epinephrine-induced signal transduction pathway.

The β-Adrenergic Receptor Kinase is recuited to the cell membrane by the Gβγ complex.

141
Q

β-Arrestin

A

A transport protein that binds to phosphorylated GPCR proteins to prevent re-association with the Gαβγ complex or initiate internalization of the receptors by endocytic vesicles.

142
Q

What process generates “docking sites” for β-Arrestin on the GPCR?

A

The phosphorylation of GPCRs by GRKs provides binding sites on the GPCR for β-Arrestin.

143
Q

What occurs to the GPCR while inside of endocytic vesicles?

A

Dephosphorylation

After dephosphorylation, the GPCR is either degraded (within the endocytic vesicle) or returned to the plasma membrane (for another round of signaling).

144
Q

Akt Protein

Protein Kinase B (PKB)

A
145
Q

Epidermal Growth Factor Receptor

EGFR

A

An RTK that binds the Epidermal Growth Factor

146
Q

Insulin Receptor Substrate

IRS

A

An adaptor protein that binds to insulin receptors

147
Q

Mitogen-Activated Protein Kinases

MAP Kinases (MAPK)

A

A trio of related kinase proteins that activate a phosphorylation cascade resulting in increased rates of eukaryotic cell division.

148
Q

How does the Ras protein transmit the EGFR signal downstrea to specific target proteins?

A

The Ras protein activates a phosphorylation cascade that is mediated by MAP Kinase proteins

149
Q

Order: MAP Kinase Pathway

A
  1. Raf
  2. MEK
  3. ERK
150
Q

Mechanism: MAP Kinase Pathway

A
  1. Ras-GTP recruits Raf to the cell membrane.
  2. Src Kinase phosphorylates Raf (at Ser/Thr residues) to activate Raf’s kinase activity.
  3. Raf phosphorylates MEK (at Ser/Thr residues) to activate MEK’s kinase activity.
  4. MEK phosphorylates ERK (at Ser/Thr residues) to activate ERK’s kinase activity.
  5. Phosphorylated ERK forms a homodiner that translocates to the nucleus and phosphorylates transcription factor proteins.
151
Q

How are EGFR-mediated signals terminated?

A
  • RasGAP Inactivation of Ras
  • Phosphatase Deactivation (of MAP Kinases or Transciption Factors)
152
Q

MAP/ERK Kinase

MEK

A

A protein kinase activated by Raf that phosphorylates ERK (at Ser/Thr residues).

MEK is the second kinase in the MAP Kinase signaling pathway.

153
Q

Extracellular Signal-Regulated Kinase

ERK

A

A protein kinase activated by MEK that translocates to the nucleus (and forms a homodimer) and phosphorylates/activates transciption factors.

ERK is the final/third kinase in the MAP Kinase signaling pathway.

154
Q

Phosphoinositide-Dependent Kinase-1

PDK1

A
155
Q

Phosphoinositide 3-Kinase

PI3K

A

An SH2-containing lipid kinase that phosphorylates PIP2 to generate PIP3 (to initiate the downstream Insulin Receptor signaling pathway).

The PI3K protein’s specificity pocket recognizes Methoinin residues at (pY + 3).

156
Q

Phosphotyrosine Binding Domain

PTB

A
157
Q

Raf Protein

A

A protein kinase that phosphorylates/activates downstream MAP Kinase target proteins (at Ser/Thr residues).

Raf is the first kinase in the MAP Kinase pathway.

158
Q

Ras Protein

A

A G Family signaling protein with intrinsic GTPase activity that functions to activate downstream signaling pathways (via phosphorylation).

The Ras protein is activated by the SOS protein (GEF) and deactivated by the RasGAP protein (GAP).

159
Q

Ras GTPase Activating Protein

RasGAP

A

A GAP that binds to the Ras protein and stimulates its intrinsic GTPase activity to generate the inactive Ras–GDP conformation.

160
Q

Src Kinase Homology–2

SH2

A

A protein domain (of about 100 amino acids) that consists of a binding site for a specific amino acid sequence containing a Phosphotyrosine residue.

The SH2 Domain also consists of a specificity pocket that recognizes amino acids a few residues away from the C-terminal side of the Phosphotyrosine.

161
Q

Src Kinase Homology–3

SH3

A

A protein domain (of about 70 amino acids) that binds to specific proline-rich sequences.

The interaction between GRB2 and SOS requires the GRB2’s SH3 domain.

162
Q

Growth Factor Receptor–Bound 2

GRB2

A

An SH2-/SH3-containing adaptor protein that binds to Phosphotyrosine residues on the EGFR.

The GRB2 protein’s specificity pocket recognizes Asparagine residues at (pY + 2).

163
Q

Son of Sevenless

SOS

A

A GEF protein that binds to and activates the Ras protein (by stimulating the GDP-for-GTP exhange reaction).

SOS must first bind to GRB2’s SH3 domains before it can activate Ras protein activity.

164
Q

What processes result in RTK activation?

A
  1. Ligand Binding
  2. Receptor Dimerization
  3. Autophosphorylation
165
Q

Which adaptor proteins are involved in upstream EGFR signaling?

A
  • GRB2
  • SOS

GRB2 and SOS function together to link the ligand-bound RTK to the Ras protein.

166
Q

Epidermal Growth Factor

EGF

A

A serum growth factor hormone that binds to the EGFR to stimulate receptor dimerization on the cell surface.

167
Q

Structural Features: Epidermal Growth Factor

A
  • 53 Amino Acids
  • 3 Disulfide Bridges
168
Q

Mechanism: EGFR Dimerization

A
  1. EGF molecules bind to both nondimerized EGFR proteins to induce receptor dimerization.
  2. EGFR dimerzation activates the kinase activity of EGFR1, which leads to EGFR1 phosphorylation of 5 Tyrosine residues in the EGFR2 cytoplasmic tail.
  3. Phosphorylation of the 5 EGFR2 C-terminal Tyrosine residues induces an EGFR-dimer conformational change that activates the EGFR2 kinase activity.
  4. EGFR2 phosphorylates the 5 Tyrosine residues in the EGFR1 cytoplasmic tail.
169
Q

2 Steps: EGFR Dimerization

A
  • Step 1: EGF binding to both EGFR monomers induces receptor dimerization that stimulates the EGFR1 kinase activity; the EGFR1 monomer subsequently phosphorylates 5 Tyrosine residues on the EGFR2 C-terminal tail.
  • Step 2: A large cytoplasmic domain conformational change (resulting from EGFR2 phosphorylation) activates the EGFR2 kinase activity; the EGFR2 monomer subsequently phosphorylates 5 Tyrosine residues on the EGFR1 C-terminal tail.
170
Q

How does GRB2 serve as a “bridging” protein?

A

GRB2 contains an SH2 domain that binds to EGFR Phosphotyrosines and two SH3 domains that bind to SOS.

GRB2 effectively links the activated EGFR to GEF signaling proteins.

171
Q

What is the cellular response to activiation of the MAP Kinase signaling pathway?

A

Increased Rates of Cell Division

172
Q

Examples: Receptor Tyrosine Kinases

A
  • Epidermal Growth Factor Receptor
  • Insulin Receptor
173
Q

Structure: Insulin Receptor

A

The Insulin Receptor is an α2β2 tetrameric complex linked together by disulfide bridges.

  • Disulfide bridges link together each αβ dimer and the two α subunits.
  • The extracellular α subunits form the Insulin-binding regions.
  • The intracellular β subunits comprise the Tyrosine kinase domains.
174
Q

How many molecules of Insulin must bind to the Insulin Receptor to stimulate receptor signaling?

A

1

The binding of a single Insulin molecule (to the Insulin Receptor) induces a receptor conformational change that decreases the binding affinity for a second Insulin molecule.

175
Q

Which three Tyrosine residues of the TK domain must be autophosphorylated before the phosphorylation of other substrates can occur?

Insulin Receptor Signaling

A
  • pY1158
  • pY1162
  • pY1163
176
Q

How many Tyrosine residues have been identified within the TK domain?

Insulin Receptor Signaling

A

7

177
Q

How does the binding of Insulin to the Insulin Receptor exhibit negative cooperativity?

A

The binding of one Insulin molecule to one α subunit inhibits the binding of another Insulin molecule to the second α subunit.

178
Q

Phosphotyrosine Binding Domain

PTB

A

A protein domain on target proteins that is used to bind to Phosphotyrosine residues on the Insulin Receptor.

179
Q

Insulin Receptor Substrate Proteins

IRS Proteins

A

A class of signaling proteins that bind to phosphorylated Insulin Receptors (at the Phosphotyrosines) through PTB domains.

180
Q

Outcomes: Insulin Receptor Downstream Signaling Pathways

A
  • MAP Kinase Pathway: Increased Glucose Uptake + Glycogen Synthesis Activation
  • PI3K Signaling Pathway: Altered Gene Expression + Increased Cell Division
181
Q

Src Homology Collagen Protein

Shc Protein

A

An adaptor protein within the Insulin Receptor signaling pathway that mediates the stimulation of cell division (via a MAP Kinase mechanism).

The Shc protein binds (via its PTB domain) to the phosphorylated Insulin Receptor and subsequently to the GRB2 protein (via GRB2’s SH2 domain).

182
Q

Phosphatidylinositol-3,4,5-Triphosphate

PIP3

A

A glycoprotein derived from the phosphorylation of PIP2 that recruits proteins with a Pleckstrin Homology domain to the cell membrane.

183
Q

Structure: PI3K

A

PI3K is a heterodimer consisting of a regulatory subunit (p85) and a catalytic subunit (p110).

  • The catalytic subunit contains two SH2 domains that bind to Phosphotyrosine residues on IRS proteins.
184
Q

Activation: PKA vs. PI3K

A
  • PKA: The binding of cAMP to PKA’s regulatory subunit activates and dissociates the catalytic subunit.
  • PI3K: The binding of PI3K’s regulatory subunit to IRS proteins activates the catalytic subunit without dissociation.
185
Q

Signaling Pathway: PKA vs. PI3K

A
  • PKA: GPCR Signaling
  • PI3K: Insulin Receptor (RTK) Signaling
186
Q

Phosphatase and Tensin Homolog

PTEN

A

A phosphatase enzyme that dephosphorylates PIP3 to regenerate PIP2 (and disrupts the downstream Insuling signaling pathway).

187
Q

Where does PIP3 situate itself after being generated?

A

Within the Cell Membrane

PIP3 remains in the cell membrane to serve as a “docking site” for PDK1 and Akt.

188
Q

Pleckstrin Homology Domain

PH Domain

A

A PTB domain in signaling proteins that binds to membrane-bound PIP3.

189
Q

Which signaling proteins possess a PH domain?

A
  • PDK1
  • Akt
190
Q

Phosphoinositide-Dependent Kinase-1

PDK1

A

A lipid kinase that binds (via its PH domain) to membrane-bound PIP3 and phosphorylates/activates the Akt protein.

191
Q

Akt

Protein Kinase B (PKB)

A

A regulatory Serine/Threonine kinase that phosphorylates downstream target proteins to decrease blood glucose level.

Akt binds (via its PH domain) to membrane-bound PIP3 and subsequently is phosphorylated/activated by PDK1.

192
Q

Binding Domains: RTK Signaling

A
  • SH2: Binds to a pY residue (and another amino acid 2-3 residues away)
  • SH3: Binds to a Proline-rich region of a target protein
  • PTB: Binds to a pY residue
  • PH Domain: Binds to a Phosphoinositol head group
193
Q

Binding Target: SH2 Domain vs. PTB Domain

A
  • SH2 Domain: Binds to a pY residue and a second amino acid 2-3 residues away from the pY.
  • PTB Domain: Binds to a pY residue only.
194
Q

What three parameters govern Nuclear Receptor signaling?

A
  • The cell-specific expresion of Nuclear Receptors (and/or coregulatory proteins)
  • The localized bioavailability of Nuclear Receptor ligands
  • The differential accessibility of Nuclear Receptors to target gene DNA sequences (within chromatin)
195
Q

What makes Nuclear Receptors unique from other receptor signaling proteins?

A

Nuclear Receptors are not membrane-bound, whereas other receptor signaling proteins are membrane-bound.

196
Q

What type of first messenger molecule binds/activates a Nuclear Receptor?

A

Lipophilic First Messenger

The binding of a lipophilic first messenger to the Nuclear Receptor ligand-binding domain causes a receptor conformational change that activates the receptor’s transcriptional regulatory functions.

197
Q

Coregulatory Protein

Coactivator/Corepressor

A

A regulatory protein that interacts with ligand-activated Nuclear Receptors to modulate rates of transcription (by modifying chromatin-associated proteins).

The coregulatory protein binds to the Nuclear Receptor after the receptor-DNA complex forms.

198
Q

Functional Domains: Nuclear Receptors

A
  • N-Terminal Domain: Binding Site for Coregulatory Protein
  • DNA-Binding Domain: Binding Site of DNA Sequences
  • C-Terminal Ligand-Binding Domain: Binding Site for Ligand and Coregulatory Protein
199
Q

Types: Nuclear Receptors

A
  • Steroid Receptors
  • Metabolite Receptors
200
Q

Examples: Steroid Receptors

A
  • Glucocorticoid Receptor
  • Estrogen Receptor
  • Progesterone Receptor
  • Androgen Receptor
  • Aldosterone Receptor
201
Q

Examples: Metabolite Receptors

A
  • Retinoid X Receptor (RXR)
  • Retinoic Acid Receptor
  • Vitamin D Receptor
  • Thyroid Hormone Receptor
  • Peroxisome Proliferator-Activated Receptor
202
Q

Steroid Receptors

A

A class of Nuclear Receptor proteins that bind to inverted repeat DNA sequences as head-to-head homodimers.

Steroid Receptors are activated by physiologic hormones derived from cholesterol (e.g. cortisol, estrogen, progesterone).

203
Q

Metabolite Receptors

A

A class of Nuclear Receptor proteins that bind to direct repeat DNA sequences as head-to-tail heterodimers.

Metabolite Receptors are activated by ligands derived from dietary nutrients (e.g. vitamins, fatty acids, amino acids).

204
Q

Spacing Between Repeat Sequences: Steroid Receptors vs. Metabolite Receptors

A
  • Steroid Receptors: 3 Nucleotides
  • Metabolite Receptors: 1–5 Nucleotides
205
Q

Retinoid X Receptor

RXR

A

A metabolite Nuclear Receptor that facilitates head-to-tail binding to direct repeat DNA sequences.

The RXR serves as the heterodimeric binding partner of most other metabolic receptors.

206
Q

Which amino acid does the Zn2+ ion coordinate to?

Zinc Finger Motif of DNA-Binding Domains

A

Cysteine

207
Q

Where on the GR is the Coregulatory Protein binding site?

A

On the Surface of the GR Ligand-Binding Domain

208
Q

Where and when are Glucocorticoids synthesized in the human body?

A

Glucocorticoids are synthesized/secreted from the adrenal glands in response to low blood glucose levels or psychological stress.

Glucocorticoid activity functions to reverse the inflammatory response caused by stress or low blood glucose.

209
Q

Why are the effects of steroids (and steroid-based pharmaceuticals) typically long-lasting?

A
  • Transciptional and translational products (of steroid-induced gene expression) takes time to return to basal levels.
  • Steroids are not easily degraded by the cell (due to being derived from Cholesterol).
  • The hydrophobicity of steroids causes them to accumulate in nonpolar cellular compartments (and increases the time required for steroid metabolism).
210
Q

Chaperonin Protein

A

A cytoplasmic protein that assists in protein folding.

211
Q

Heat Shock Protein 90

Hsp90

A

An abundant chaperonin protein in cells involved in Nuclear Receptor signaling (and numerous other pathways).

212
Q

Glucocorticoid Response Element

GRE

A

The DNA cis-acting/inverted sequence located near Glucocorticoid-regulated genes that functions as the binding site for ligand-activated Glucocorticoid Receptors.

213
Q

What pathway does the Glucocorticoid Receptor signaling regulate?

A

Anti-Inflammatory Pathway

214
Q

Mechanism: Glucocorticoid-Mediated Inflammation Reduction

A
  1. Glucocorticoids cross the cell membrane and bind to inactive-form intracellular/cytoplasmic Glucocorticoid Receptors.
  2. The GR is released from the inactive chaperonin complex (that contains the Hsp90 protein).
  3. GR translocates to the nucleus and either forms a homodimer that binds to the Annexin I regulatory region or binds to the p65 NFκB subunit as a monomer.
215
Q

Examples: Enzymatic Receptor Proteins

A
  • Receptor Tyrosine Kinases
  • Receptor Guanylyl/Guanylate Cyclases
  • Receptor Adenylyl/Adenylate Cyclases
216
Q

Where does Nuclear Receptor contact with DNA sequences typically occur?

A

Within the Major Grooves

217
Q

Types of Phosphatases: Insulin Signaling Pathway

A
  • Serine Phosphatases: Dephosphorylate Actived Akt
  • Lipid Phosphatases: Dephosphorylate PIP3 (PTEN)
  • Tyrosine Phosphatases: Dephosphorylate Activated RTK
218
Q
A

Biochemistry (7 decks)

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