Module 3 Flashcards

Question

Phospholipases

Answer 1

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

Answer 2

A long-chain amino alcohol synthesize from palmitate and serine. ## Footnote **Sphingolipids** are derived from sphingosine.

Answer 3

A sphingosine molecule covalently linked to a fatty acid chain that serves as the precursor for sphingophospholipids and sphingoglycolipids. ## Footnote * **Sphingophospholipid:** Phosphocholine + Ceramide * **Cerebroside:** Monoglycosylated Ceramide * **Ganglioside:** Oligoglycosylated Ceramide

Answer 4

Cholesterol

Answer 5

Carrier Proteins

Answer 6

* Channel Proteins * Carrier Proteins

Answer 7

* **Channel Proteins:** Slower than Diffusion * **Carrier Proteins:** Comparable to Diffusion

Answer 8

* **Channel Proteins:** Semiselective * **Carrier Proteins:** Highly Selective

Answer 9

**Carrier proteins** can become saturated at high substrate/ligand concentrations (due to their slow rate of biomolecule translocation). ## Footnote **Channel proteins** do NOT usually become saturated with substrate, so their rate of biomolecule translocation increases with increasing [substrate].

Answer 10

## Footnote * **R:** Gas Constant * **T:** Temperature * **C₂:** End-Point Concentration * **C₁:** Start-Point Concentration * **Z:** Charge of Solute Molecule * **F:** Faraday Constant * **V:** Membrane Potential

Answer 11

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

Answer 12

A passive membrane transport channel protein that possesses a *β-barrel* structural motif and is organized as a *homotrimer*. ## Footnote * Porins are abundant in the outer membranes of **bacteria**, **mitochondria**, and **chloroplasts**. * Porins are permeable to **ions** and **small molecules**.

Answer 13

* **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.

Answer 14

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).

Answer 15

Nonspecific porin molecules that allow for molecular passage *solely* according to the size of the transported molecule. ## Footnote The inner diameter size of non-selective porins is determined by the number of β-strands the channel consists of.

Answer 16

Highly specific porin molecules that permit molecular passage based on the chemical characteristics of the transported molecule. ## Footnote The chemical proporties of the porin's inner-facing hydrophilic amino acid side chains determine the channel's specificity for particular molecules.

Answer 17

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

Answer 18

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

Answer 19

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

Answer 20

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

Answer 21

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

Answer 22

An *active* transport protein that uses the hydrolysis of ATP to drive molecules across membranes *against* their concentration gradient. ## Footnote Primary active transporters typically undergo **significant conformational changes** (powered by ATP hydrolysis) to transport molecules across membranes.

Answer 23

* P-Type (Phosphorylated-Type) Transporters * ATP-Binding Cassette (ABC) Transporters

Answer 24

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

Answer 25

A *primary* active membrane transport protein that **hydrolyzes ATP** (*without* becoming become phosphorylated) to drive large conformational changes and pump molecules across the membrane. ## Footnote ABC Transporter conformational changes include the conversion from an outward-facing transporter to an inward-facing transporter.

Answer 26

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. ## Footnote 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.

Answer 27

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

Answer 28

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

Answer 29

A P-type primary active transporter responsible for pumping H⁺ ions into the stomach to lower the pH of gastric juices. ## Footnote The H⁺–K⁺ ATPase uses energy from ATP hydrolysis to exchange H⁺ ions and K⁺ ions across the cell membrane.

Answer 30

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

Answer 31

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

Answer 32

* **M:** Transmembrane Domain * **A:** Regulatory Domain * **P:** Phosphoryl Domain * **N:** ATP-Binding Domain ## Footnote SERCA transporters and Na⁺–K⁺ ATPases consist of the *same* general domain structures.

Answer 33

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

Answer 34

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 Ca^{2+^{into the SR**.

## Footnote

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

Answer 35

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

Answer 36

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

Answer 37

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.

Answer 38

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

Answer 39

Cancer cells can become resistant to chemotherapy drugs by increasing the number of Multidrug Resistance Proteins (MRPs) in the cell membrane. ## Footnote The high quantity of MRPs causes the removal the chemotherapy drug(s) from the cell become they can become effective.

Answer 40

* P-Glycoprotein Transporter * CFTR Protein * *A. Fulgidus* Molybdate Transporter * *E. Coli* Maltose Transporter

Answer 41

* **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.

Answer 42

* **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.

Answer 43

* Periplasmic Side (of Transmembrane Domain) * Transmembrane Domain * Nucleotide-Binding Domain ## Footnote * 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.

Answer 44

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 + P_i within the nucleotide-binding domains to regenerate the ABC Transporter resting state.

Answer 45

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 + P_i** from the ABC Transporter and subsequent **binding of ATP** to the ABC Transporter regenerates the resting state conformation.

Answer 46

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

Answer 47

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

Answer 48

* Lactose Permease Symporter * Na⁺–I^– Symporter

Answer 49

A secondary active transport protein in thyroid gland cells that imports Iodide (I^–) ions into cells for thyroid hormone synthesis. ## Footnote The Na⁺–I^– Symporter imports one I^– ion into the cell for every two Na⁺ imported.

Answer 50

Na⁺–K⁺ ATPase (Primary Active Transporter)

Answer 51

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

Answer 52

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

Answer 53

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

Answer 54

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

Answer 55

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

Answer 56

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

Answer 57

A protein that transmits a biochemical signal from a *receptor protein to a second messenger* or from a *second messenger to a target protein*. ## Footnote * **Upstream signaling proteins** transmit biochemical signals from receptor proteins to second messengers. * **Downstream signaling proteins** transmit biochemical signals from second messengers to target proteins.

Answer 58

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*.

Answer 59

A biologically active compound released into the circulatory system that binds to hormone receptors within/on target cells. ## Footnote Hormones are a type of **first messenger**.

Answer 60

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

Answer 61

* Acetylchloine * Cortisol * Epidermal Growth Factor (EGF) * Epinephrine/Adrenaline * Glucagon * Insulin * Testosterone * Prostaglandins * β-Estradiol/Estrogen * Ca^{2+^{* CO₂
* NO (Nitric Oxide)
* Amino Acids
* Nucleotides}}

Answer 62

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

Answer 63

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

Answer 64

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

Answer 65

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

Answer 66

A catalytic enzyme that *hydrolyzes* cGMP.

Answer 67

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

Answer 68

A membrane-bound enzymatic receptor that produces cGMP from GTP. ## Footnote The intracellular Guanylyl Cyclase domain serves as the catalying/cGMP-forming region.

Answer 69

A membrane-bound enzymatic receptor that produces cAMP from ATP. ## Footnote The intracellular Auanylyl Cyclase domain serves as the catalying/cGMP-forming region.

Answer 70

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

Answer 71

* cGMP * cAMP * DAG * IP₃ * Ca²⁺

Answer 72

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

Answer 73

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

Answer 74

A membrane-associated enzyme responsible for controlling the intracellular levels of DAG and IP₃. ## Footnote Phospholipase C hydrolyzes PIP₂ to form DAG and IP₃.

Answer 75

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

Answer 76

A kinase protein that phosphorylates downstream target molecules (of a cell signaling pathway) after being activated by DAG. ## Footnote Protein Kinase C can be activated via binding of 2 Ca²⁺ ions.

Answer 77

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

Answer 78

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.

Answer 79

* G Protein-Coupled Receptors * Receptor Tyrosine Kinases * Tumor Necrosis Factor Receptors * Nuclear Receptors * Ligand-Gated Ion Channels

Answer 80

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

Answer 81

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). ## Footnote Receptor Tyrosine Kinases signal through adaptor proteins that bind phosphotyrosine residues on the receptor's intracellular domain.

Answer 82

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

Answer 83

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

Answer 84

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

Answer 85

* Glucocorticoid Receptor * Vitamin D Receptor

Answer 86

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

Answer 87

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.

Answer 88

* 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.

Answer 89

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

Answer 90

A GPCR consisting of 7 transmembrane α-helices and a bound retinal molecules that absorbs light. ## Footnote **Rhodopsin** transduces light signals (sensed by the retinal light sensor) to cytosolic signaling proteins through receptor-mediated conformational changes.

Answer 91

A membrane-bound protein complex associated with a GPCR that dissociates (upon ligand binding to the GPCR) to initiate downstream signaling pathways. ## Footnote The **heterotrimeric G protein** consists of one G_α subunit, one G_β subunit, and one G_γ subunit.

Answer 92

* **Active:** The G_α is bound to GTP. * **Inactive:** The G_α is bound to GDP.

Answer 93

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

Answer 94

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

Answer 95

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 G_α subunit, which leads to G Protein **dissociation into G_α-GTP and G_βγ**. 3. G_α-GTP and G_βγ stimulate/regulate **downstream signaling** processes.

Answer 96

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

Answer 97

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

Answer 98

* Epinephrine/Adrenaline * Norepinephrine/Noradrenaline * Dopamine

Answer 99

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

Answer 100

A compound that binds to and deactivates/blocks a receptor protein by preventing the binding of the natural receptor. ## Footnote The binding of the receptor antagonist (to the receptor) prevents structural changes form occurring within the receptor that would initiate signal transduction mechanisms.

Answer 101

The exchange of GDP for GTP within the G_sα subunit induces a G_sα conformational change that allows it to bind Adenylate Cyclase. ## Footnote The Switch II Helix region of G_sα (originally bound to the inactive G_βγ complex) undergoes a conformational change in the presence of bound GTP such that G_sα is able to interact with Adenylate Cyclase.

Answer 102

Activation of Protein Kinase A

Answer 103

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

Answer 104

R₂C₂ Tetramer (2 Regulatory Subunits + 2 Catalytic Subunits) ## Footnote Activation of PKA occurs when 2 cAMP molecules bind to each regulatory subunit to release the active catalytic subunits.

Answer 105

* Phosphorylation/**Inhbition** of Glycogen Synthase * Phosphorylation/**Activation** of Glycogen Degredation Enzymes * Phosphorylation/**Activation** of Gluconeogensis Enzymes

Answer 106

* Phosphorylation/**Inhbition** of Glycogen Synthase * Phosphorylation/**Activation** of Glycogen Degredation Enzymes

Answer 107

The binding of Rac/G_qα (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.

Answer 108

A protein that promotes GDP-to-GTP exchange within the G_α subunit to activate downstream signaling mechanisms. ## Footnote The activity of **Guanine Nucleotide Exchange Factors** is countered by GTPase Activating Proteins.

Answer 109

A protein that stimulates the intrisinic GTP-hydrolyzing activity of G_α proteins to inhibit downstream signaling mechanisms. ## Footnote The activity of **GTPase Activating Proteins** is countered by Guanine Nucleotide Exchange Factors.

Answer 110

A GAP that functions with G_α Proteins associated with GPCRs.

Answer 111

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

Answer 112

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

Answer 113

* G_α-Mediated GTP Hydrolysis * GPCR Desensitization via GRKs * Feedback Inhibition via PKA Phosphorylation

Answer 114

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

Answer 115

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. ## Footnote The β-Adrenergic Receptor Kinase is recuited to the cell membrane by the G_βγ complex.

Answer 116

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

Answer 117

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

Answer 118

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

Answer 119

An RTK that binds the Epidermal Growth Factor

Answer 120

An adaptor protein that binds to insulin receptors

Answer 121

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

Answer 122

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

Answer 123

1. Raf 2. MEK 3. ERK

Answer 124

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.

Answer 125

* RasGAP Inactivation of Ras * Phosphatase Deactivation (of MAP Kinases or Transciption Factors)

Answer 126

A protein kinase activated by Raf that phosphorylates ERK (at Ser/Thr residues). ## Footnote MEK is the second kinase in the MAP Kinase signaling pathway.

Answer 127

A protein kinase activated by MEK that translocates to the nucleus (and forms a homodimer) and phosphorylates/activates transciption factors. ## Footnote ERK is the final/third kinase in the MAP Kinase signaling pathway.

Answer 128

An SH2-containing lipid kinase that phosphorylates PIP₂ to generate PIP₃ (to initiate the downstream Insulin Receptor signaling pathway). ## Footnote The PI3K protein's specificity pocket recognizes Methoinin residues at (pY + 3).

Answer 129

A protein kinase that phosphorylates/activates downstream MAP Kinase target proteins (at Ser/Thr residues). ## Footnote Raf is the first kinase in the MAP Kinase pathway.

Answer 130

A G Family signaling protein with intrinsic GTPase activity that functions to activate downstream signaling pathways (via phosphorylation). ## Footnote The **Ras protein** is activated by the SOS protein (GEF) and deactivated by the RasGAP protein (GAP).

Answer 131

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

Answer 132

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

Answer 133

A protein domain (of about 70 amino acids) that binds to specific proline-rich sequences. ## Footnote The interaction between GRB2 and SOS requires the GRB2's SH3 domain.

Answer 134

An SH2-/SH3-containing adaptor protein that binds to Phosphotyrosine residues on the EGFR. ## Footnote The GRB2 protein's specificity pocket recognizes Asparagine residues at (pY + 2).

Answer 135

A GEF protein that binds to and activates the Ras protein (by stimulating the GDP-for-GTP exhange reaction). ## Footnote SOS must first bind to GRB2's SH3 domains before it can activate Ras protein activity.

Answer 136

1. Ligand Binding 2. Receptor Dimerization 3. Autophosphorylation

Answer 137

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

Answer 138

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

Answer 139

* 53 Amino Acids * 3 Disulfide Bridges

Answer 140

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.

Answer 141

* **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.

Answer 142

GRB2 contains an *SH2 domain that binds to EGFR Phosphotyrosines* and *two SH3 domains that bind to SOS*. ## Footnote **GRB2** effectively links the activated EGFR to GEF signaling proteins.

Answer 143

Increased Rates of Cell Division

Answer 144

* Epidermal Growth Factor Receptor * Insulin Receptor

Answer 145

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

Answer 146

1 ## Footnote 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.

Answer 147

* pY1158 * pY1162 * pY1163

Answer 148

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

Answer 149

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

Answer 150

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

Answer 151

* **MAP Kinase Pathway:** Increased Glucose Uptake + Glycogen Synthesis Activation * **PI3K Signaling Pathway:** Altered Gene Expression + Increased Cell Division

Answer 152

An adaptor protein within the Insulin Receptor signaling pathway that mediates the stimulation of cell division (via a MAP Kinase mechanism). ## Footnote The Shc protein binds (via its PTB domain) to the phosphorylated Insulin Receptor and subsequently to the GRB2 protein (via GRB2's SH2 domain).

Answer 153

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

Answer 154

PI3K is a **heterodimer** consisting of a **regulatory subunit** (p85) and a **catalytic subunit** (p110). ## Footnote * The catalytic subunit contains two SH2 domains that bind to Phosphotyrosine residues on IRS proteins.

Answer 155

* **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*.

Answer 156

* **PKA:** GPCR Signaling * **PI3K:** Insulin Receptor (RTK) Signaling

Answer 157

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

Answer 158

Within the Cell Membrane ## Footnote PIP₃ remains in the cell membrane to serve as a "docking site" for **PDK1** and **Akt**.

Answer 159

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

Answer 160

* PDK1 * Akt

Answer 161

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

Answer 162

A regulatory Serine/Threonine kinase that phosphorylates downstream target proteins to decrease blood glucose level. ## Footnote Akt binds (via its PH domain) to membrane-bound PIP₃ and subsequently is phosphorylated/activated by PDK1.

Answer 163

* **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

Answer 164

* **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*.

Answer 165

* 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)

Answer 166

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

Answer 167

*Lipophilic* First Messenger ## Footnote 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.

Answer 168

A regulatory protein that interacts with ligand-activated Nuclear Receptors to modulate rates of transcription (by modifying chromatin-associated proteins). ## Footnote The coregulatory protein binds to the Nuclear Receptor *after* the receptor-DNA complex forms.

Answer 169

* **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

Answer 170

* Steroid Receptors * Metabolite Receptors

Answer 171

* Glucocorticoid Receptor * Estrogen Receptor * Progesterone Receptor * Androgen Receptor * Aldosterone Receptor

Answer 172

* Retinoid X Receptor (RXR) * Retinoic Acid Receptor * Vitamin D Receptor * Thyroid Hormone Receptor * Peroxisome Proliferator-Activated Receptor

Answer 173

A class of Nuclear Receptor proteins that bind to *inverted repeat* DNA sequences as head-to-head *homodimers*. ## Footnote Steroid Receptors are activated by physiologic hormones derived from cholesterol (e.g. cortisol, estrogen, progesterone).

Answer 174

A class of Nuclear Receptor proteins that bind to *direct repeat* DNA sequences as head-to-tail *heterodimers*. ## Footnote Metabolite Receptors are activated by ligands derived from dietary nutrients (e.g. vitamins, fatty acids, amino acids).

Answer 175

* **Steroid Receptors:** 3 Nucleotides * **Metabolite Receptors:** 1–5 Nucleotides

Answer 176

A *metabolite* Nuclear Receptor that facilitates head-to-tail binding to *direct repeat* DNA sequences. ## Footnote The **RXR** serves as the heterodimeric binding partner of most other metabolic receptors.

Answer 177

On the Surface of the GR Ligand-Binding Domain

Answer 178

Glucocorticoids are synthesized/secreted from the **adrenal glands** in response to **low blood glucose** levels or **psychological stress**. ## Footnote Glucocorticoid activity functions to reverse the inflammatory response caused by *stress* or *low blood glucose*.

Answer 179

* 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).

Answer 180

A cytoplasmic protein that assists in protein folding.

Answer 181

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

Answer 182

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

Answer 183

Anti-Inflammatory Pathway

Answer 184

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*.

Answer 185

* Receptor Tyrosine Kinases * Receptor Guanylyl/Guanylate Cyclases * Receptor Adenylyl/Adenylate Cyclases

Answer 186

Within the Major Grooves

Answer 187

* **Serine Phosphatases:** Dephosphorylate Actived Akt * **Lipid Phosphatases:** Dephosphorylate PIP₃ (PTEN) * **Tyrosine Phosphatases:** Dephosphorylate Activated RTK