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BIOC4332: Biochemistry II > Exam IV > Flashcards

Exam IV Flashcards

1
Q

What is signal transduction?

A

The conversion of an extracellular input to an intracellular output

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2
Q

Cells are exposed to many extracellular stimuli. What does this mean for the cell?

A

The combination of inputs a cell receives can dictate its fate (Lives, proliferates, differentiates, dies, etc.)

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3
Q

Cell signaling enables transmission from _____ to _____.

A

outside of the cell; nucleus

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4
Q

Cell signaling turns on and off [slowly/quickly] while gene expression turns on and off [slowly/quickly].

A

quickly; slowly

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5
Q

Between cell signaling and gene expression, which is more energetically costly?

A

Gene expression (Transcription and translation)

Cell signaling is energetically cheap because there’s no protein synthesis

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6
Q

What are the principal mechanisms of state change?

A
  1. Binding/dissociation
  2. Post-translational modification
  3. Conformational change
  4. Localization
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7
Q

For Src kinase, what is the input signal?

A

A phosphatase that removes the pTyr527 modiification

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8
Q

For Src kinase, what is the output signal?

A

An active kinase domain that phosphorylates downstream proteins

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9
Q

How does buried surface area relate to protein-protein interactions?

A

A larger buried SA means stronger binding interaction

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10
Q

True or false? The end goal of binding interactions in signaling pathways is to be as avid (high affinity) and specific (high specificity) as possible, so as we look back at the evolution of signaling pathways, we see a trend in this direction.

A

False.

Some organisms may have signaling pathways that are more promiscuous or have lower specificity to allow for flexibility in responding to a range of signals.

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11
Q

How is the Kd of an interaction matched to the physiological concentration of the molecules involved?

A

Increasing the local concentration of a biomolecule can increase the likelihood of binding

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12
Q

What is allosteric regulation?

A

A state change to a protein caused by binding of a ligand outside of the active site

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13
Q

Membrane localization can dramatically [decrease/increase] the relative concentration of signaling molecules.

A

increase

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14
Q

What is the logic behind post-translational modifications?

A
  1. Fast
  2. Energetically cheap
  3. Usually reversible
  4. Combinatorial
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15
Q

What chemical effects do post-translational modifications have?

A

Changes size, shape, charge of amino acid side chains, hydrophobicity, and hydrophilicity

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16
Q

Name five post-translational modifications aside from phosphorylation.

A
  1. Glycosylation (Sugar)
  2. S-palmitoylation (Lipids)
  3. Isomerization (Proline residues)
  4. Ubiquitinatin/sumoylation (Proteins)
  5. Degradation
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17
Q

What are five effects of post-translational modification on cell signaling?

A
  1. Change conformation
  2. Promote binding
  3. Prevent binding
  4. Change subcellular localization
  5. Change proteolytic stability
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18
Q

In signal pathway diagrams, a double negative means what?

A

Positive

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19
Q

What is the difference between coherent and incoherent feedforward?

A

Coherent: Two pathways lead to the same output

Incoherent: One pathway leads to the output and the other represses it

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20
Q

How does half life relate to the duration of cell signaling?

A

The concentration of components with longer half lives take longer to fall after synthesis rate drops

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21
Q

How does the concentration of signaling components with short half lives change?

A

It changes rapidly when the synthesis rate increases or decreases

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22
Q

The speed of response and duration of signaling depend on what?

A

The rate of synthesis and degradation of signaling molecules

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23
Q

Maximum output is determined by what?

A

The amount of signaling protein

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24
Q

How do coherent feedforward motifs with an “AND” gate sense sustained input?

A

Both the slow AND fast paths must occur at the same time to produce output

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25
Q

Describe the three desensitization adaptations in cell signaling.

A
  1. Receptor sequestration: Receptor is sent into an endosome but recycles back to the membrane
  2. Receptor down-regulation: Receptor is sent to an endosome, then to a lysocome to be degraded. New synthesis is required to restore receptors.
  3. Receptor inactivation, inactivation of signaling protein, production of inhibitoary protein: Inhibition
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26
Q

What are the four ways extracellular signals can act over short or long distances?

A
  1. Contact-dependent
  2. Paracrine: Releasing signaling molecules that bind to surrounding cells
  3. Synaptic
  4. Endocrine: Cell targets a distant cell through the bloodstream
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27
Q

What are the common classes of hormones?

A
  1. Amine (Norephinephrine)
  2. Peptide (Oxytocin)
  3. Protein (Human growth hormone)
  4. Steroid (Testosterone, progesterone)
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27
Q

[Hydrophobic/hydrophilic] molecules can pass through the cell membrane to intracellular receptors.

A

Hydrophobic

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27
Q

[Hydrophobic/hydrophilic] molecules can’t pass through the cell membrane and need ______ to relay the information.

A

Hydrophilic; cell-surface receptors

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27
Q

Define an antagonist.

A

A ligand that blocks the actions of the agonist by competitively binding to the receptor

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28
Q

What are the four major classes of receptors?

A
  1. GPCRs
  2. Enzyme-linked
  3. Ion-channel
  4. Intracellular
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28
Q

Define an agonist.

A

A ligand that activates a receptor

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29
Q

Describe how GPCRs work.

A

Ligand binds to receptor, causing a conformational change. This creates a binding pocket in the receptor inside of the cell for the next protein.

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30
Q

Describe how enzyme-linked receptors work.

A

Inactive: Two parts of the receptor are unbound

Active: Ligand binds, bringing the two parts together and activating the receptor

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31
Q

Describe how ion-channel receptors work.

A

Inactive: Channel is closed

Active: Ligand binds, opening the channel and allowing ions to flow through

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32
Q

Describe how intracellular receptors work.

A

Ligand goes through the cell membrane and into the cytoplasm, binding to an intracellular receptor.

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33
Q

Briefly describe what happens when a GPCR is activated.

A

Alpha subunit in trimeric G protein is activated, releasing the beta and gamma subunits to go and activate other proteins

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34
Q

Drugs aimed at specific [receptor class] are among the most effective and common pharmaceuticals.

A

GPCRs

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35
Q

True or false. GPCRs are highly specific and recognize only a limited amount of ligands.

A

False.

GPCRs recognize an enormous diversity of ligands with very different physical natures.

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36
Q

How many transmembrane domains do GPCRs have?

A

Seven

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37
Q

Describe the transmembrane domains in GPCRs.

A
  1. 24-25 aa long
  2. Hydrophobic
  3. Alpha-helical
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38
Q

What part of the transmembrane domains in GPCRs is especially important for activating the alpha subunit?

A

The intracellular loop between helices 5 and 6

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39
Q

What is the effect of conformational changes in the extracellular ligand binding domain in GPCRs?

A

It also causes conformational changes in the intracellular GEF domain through the transmembrane helices (Think marionette puppets)

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40
Q

What are G proteins?

A

Signaling proteins that bind guanine nucleotides and function as molecular switches

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41
Q

When are GTP-binding proteins active and inactive?

A

Active: Bound to GTP

Inactive: Bound to GDP or nothing

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42
Q

The presence of what molecule induces the conformational change in G-proteins?

A

Gamma-phosphate

(Without it, it’s GDP-bound. With it, it’s GTP-bound and active.)

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43
Q

What are the two major types of G-proteins?

A

Monomeric and heterotrimeric

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44
Q

Where are trimeric G-proteins in the cell?

A

Attached to the plasma membrane

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45
Q

GDP is bound to the alpha subunit. Is the G-protein active or inactive?

A

Inactive

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46
Q

How are G-proteins attached to the plasma membrane?

A

The alpha and gamma units are linked to the membrane by covalently attached fatty acid and isoprenoid units, respectively.

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47
Q

What kind of enzyme is the alpha unit of a G protein?

A

GTPase (Hydrolases that bind GTP and hydrolyze it to GDP)

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48
Q

What are the two domains of the alpha subunit in G proteins?

A
  1. Ras domain (Forms one face of binding pocket)
  2. Alpha helical domain (Forms the other side of the guanine nucleotide binding pocket)
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49
Q

What are the three major types of G proteins?

A
  1. Gs
  2. Gi
  3. Gq
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50
Q

What is the function of the G-protein Gs?

A

Activates adenylyl cyclase and activates Ca2+ channels

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51
Q

What is the function of the G-protein Gi?

A

Inhibits adenylyl cyclase

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52
Q

What is the function of the G-protein Gq?

A

Activates phospholipase C-beta

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53
Q

Describe the four steps of the activation of a G-protein by an activated GPCR.

A
  1. Ligand binds to GPCR, causing a conformational change that allows the G protein to bind to it.
  2. Binding of the G protein alters the G protein’s conformation, and the AH domain of the alpha subunit moves out, letting GDP escape.
  3. GTP binding to the alpha subunit closes the binding pocket, causing a conformational change that releases the beta-gamma subunit.
  4. The freed up alpha and beta-gamma subunits can now regulate downstream effector molecules.
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54
Q

A GPCR stays active as long as what?

A

As long as ligand is bound, allowing it to activate many G proteins

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55
Q

Describe the four steps in which GPCR signaling activates adenylyl cyclase in response to epinephrine.

A
  1. Epinephrine binds GPCR
  2. Conformational change in GPCR accelerates the exchange of GDP to GTP, activating the Gs-alpha subunit.
  3. GTP-bound Gs-alpha subunit binds and activates adenylyl cyclase
  4. Activated adenylyl cyclase converts ATP to cAMP, a second messenger
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56
Q

cAMP is hydrolyzed by ____ to form 5’-AMP.

A

phosphodiesterases (PDEs)

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57
Q

What are three hormone-induced responses mediated by cyclic AMP?

A
  1. Adrenaline causes glycogen breakdown in muscles
  2. Glucagon causes glycogen breakdown in the liver
  3. Adrenaline, ACTH, glucagon, and TSH causes triglyceride breakdown in fat
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58
Q

How does cAMP allosterically activate protein kinase A?

A

cAMP binds to the two regulatory subunits of PKA, releasing the two catalytic subunits, which are now active.

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59
Q

Protein kinase A is dependent on what molecule for activation?

A

cAMP

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60
Q

What kind of kinase is protein kinase A?

A

Serine/threonine protein kinase

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61
Q

Describe the subunits of protein kinase A in the absence of cAMP.

A

The catalytic subunits are bound to regulatory subunits, which inhibit catalytic activity.

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62
Q

What is the immediate response to the activation of protein kinase A?

A

Phosphorylation of many proteins

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63
Q

What does CRE stand for?

A

cAMP response element

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64
Q

What does CREB stand for?

A

cAMP response element binding protein

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65
Q

What does CBP stand for?

A

CREB-binding protein

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66
Q

Describe the role that CRE, CREB, and CBP play in activating gene transcription.

A
  1. Activated protein kinase A phosphorylates an inactive CREB, activating it
  2. CBP can now bind to an active CREB
  3. CBP-CREB complex binds to CRE on the DNA upstream from the now activated target gene, leading to transcription
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67
Q

Active adenylyl cyclase produces cAMP, activating protein kinase A.

How does this lead to increased glycogen breakdown?

A

PKA phosphorylates and activates glycogen phosphorylase kinase, which phosphorylates and activates glycogen phosphorylase, leading to glycogen breakdown.

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68
Q

Active adenylyl cyclase produces cAMP, activating protein kinase A.

How does this lead to increased gluconeogenesis?

A

PKA phosphorylates CREB, a transcription activator, leading to increased PEPCK transcription and increased gluconeogenesis

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69
Q

What affect does Gi-alpha have on adenylyl cyclase?

A

An inhibitory hormone binds to the receptor, activating the inhibitory G protein, which turns adenylyl cyclase off (No cAMP production)

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70
Q

What is the function of cAMP phosphodiesterase (PDE)?

A

It resets cAMP signaling by catalyzing a hydrolysis reaction to convert cAMP into AMP

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71
Q

What are two bacterial toxins that hijack G-protein signaling?

A

Cholera and pertussis (Whooping cough)

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72
Q

How does cholera affect G-protein signaling?

A

It locks Gs-alpha in an active state.

The A1 subunit of cholera catalyzes the ADP-ribosylation of Gs-alpha, making it unable to hydrolyze GTP.

This leads to increased cAMP levels.

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73
Q

How does pertussis affect G-protein signaling?

A

It locks Gi-alpha in an inactive state.

A pertussis subunit catalyzes the ADP-ribosylation of Gi-alpha, making it unable to interact with GEFs.

This leads to elevated cAMP levels and overactive PKA.

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74
Q

What is the function of phospholipases?

A

They hydrolyze membrane phospholipids at different positions in the molecule

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75
Q

Where do phospholipase C’s cleave?

A

The phosphodiester bond between the glycerol backbone and phosphate head group

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76
Q

What happens when phospholipase C-beta cleaves PIP2? What is produced?

A

PIP2 is cleaved into the secondary messengers diacylglycerol and IP3.

Diacylglycerol is still attached to the membrane and activates protein kinase C.

IP3 releases Ca2+ from the ER. Ca2+ also activates PKC.

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77
Q

How does IP3 release Ca2+ from the ER?

A

IP3 is very water soluble and diffuses through the cytoplasm to the ER membrane, where it stimulates an IP3-gated calcium channel

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78
Q

What two molecules are required to activate protein kinase C?

A

Diacylglycerol and calcium

(C is for calcium)

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79
Q

Why is PKC recruited to the membrane?

A

Diacylglycerol is required to activate PKC, and it’s bound to the membrane.

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80
Q

What is the function of the C1 and C2 domains in protein kinase C?

A

They keep PKC inhibited.

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81
Q

What does an activated Gq activate?

A

Phospholipase C-beta

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82
Q

Diacylglycerol is the precursor for what two molecules?

A

Arachidonic acid and prostaglandins (PGs)

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83
Q

What do “EF hand” domains bind to?

A

Ca2+

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84
Q

What is the function of calmodulin (CaM)?

A

It’s a major mediator of Ca2+ signaling.

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85
Q

How does calmodulin work?

A

When calcium-bound, it forms a barbell shape. The exposed central helix has an affinity for target proteins and will wrap around them.

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86
Q

How does GPCR kinase (GRK) desensitize GPCRs?

A

GRKs phosphoylates GPCR on multiple sites.

Arrestin binds to phosphorylated GPCR, desensitizing GPCR.

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87
Q

What are enzyme-coupled receptors?

A

Transmembrane proteins with single membrane spanning domains

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88
Q

How are enzyme-coupled receptors activated?

A

Substrate binding causes dimerization (Two domains coming together). These dimers are active.

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89
Q

Name the five types of enzyme-coupled receptors.

A
  1. Receptor tyrosine kinases (RTKs)
  2. Tyrosine kinase-associated receptors
  3. Receptor serine/threonine kinases
  4. Receptor guanylyl cyclases
  5. Receptor tyrosine phosphatases
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90
Q

What is the function of receptor tyrosine kinases (RTKs)?

A

Phosphorylate on specific tyrosines (Growth factor receptors)

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91
Q

What is the function of tyrosine kinase-associated receptors?

A

Non-covalent association with intracellular tyrosine kinases (Cytokine receptors)

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92
Q

What is the function of receptor serine/threonine kinases?

A

Phosphorylate specific serines or threonines (TBF-beta receptors)

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93
Q

What is the function of receptor guanylyl cyclases?

A

Synthesize cGMP

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94
Q

What is the function of receptor tyrosine phosphatases?

A

Remove phosphate from tyrosines

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95
Q

What is the most abundant type of enzyme-coupled receptor?

A

Receptor tyrosine kinases (RTKs)

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96
Q

For receptor tyrosine kinases, is the tyrosine kinase domain inside or outside the cell?

A

Inside

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97
Q

How many times do RTKs span the membrane?

A

Once

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97
Q

True or false? RTKs are dimers in the absense of a ligand.

A

False. They’re monomers when inactive and dimers when active.

97
Q

What do RTKs regulate?

A

Cell proliferation, growth, differentiation, migration, and fate

98
Q

What are four mechanisms of dimerization for RTKs?

A
  1. Ligand is a dimer and simutaneously binds to two receptors.
  2. A monomeric ligand binds to two receptors, bringing them together.
  3. Two ligands bind to two receptors and bring them together.
  4. The ligand is already a dimer and induces a conformational change, activating the kinase activity.
99
Q

Describe the inactive state of RTKs.

A

RTKs are monomers anchored in the plasma membrane by a single transmembrane domain (Except insulin receptor, which has two)

100
Q

What happens when a ligand binds to a RTK?

A

The receptor monomers dimerize, activating the tyrosine kinase activity of one/both monomers.

101
Q

What are the two mechanisms by which dimerization of RTKs activates tyrosine kinase activity?

A
  1. Cross phosphorylation: Activated tyr kinase domains phosphorylate each other
  2. Conformational changes in the domain in response to ligand binding lead to one tyr domain (Activator) activating the other (Receiver). The receiver phosphorylates both subunits.
102
Q

What occurs once the internal domains of the RTK are phosphorylated?

A

The domains serve as docking sites for signaling proteins

103
Q

Describe the structure of SH2 domains.

A

Central beta-sheet separating two alpha-helices

One binding site on each side of the beta-sheet. One for amino acid side chain (specificity) and one for phosphotyrosine.

104
Q

Describe the structure of PTB domains.

A

Two orthogonal beta-sheets form a sandwich, capped by a C-terminal alpha-helix

105
Q

A single RTK can have many phosphorylation sites that recruit what?

A

SH2 or PTB domain-containing proteins

106
Q

What is the function of adapter proteins in relation to RTKs?

A

Adaptors have binding domains that scaffold multiple proteins, bringing them closer

107
Q

What is Grb2?

A

An adaptor that binds to RTKs

Composed of a central SH2 domain surrounded by two SH3 domains

108
Q

What do SH3 domains bind to?

A

Proline-rich regions

109
Q

Describe the structure of SH3 domains.

A

Contain two binding groves. One binds to proline and the other to hydrophobic amino acid.

110
Q

PTB binds preferentially to what motif?

A

NPxpY

x = Any amino acid
pY = Phosphotyrosine

111
Q

What are the common recognition motifs for SH3 domains?

A

Polyproline type II (PPII) heclies

PxxP sequences

112
Q

How do RTKs become oncogenic?

A

They can mutate, becoming dimerized and active without the ligand. The external domain can be truncated, which also activates the receptor without the ligand.

113
Q

Src protein kinases are all [cytosolic/extracellular] tyrosine kinases.

A

cytosolic

114
Q

What happens when SH2 and SH3 domains bind to Src?

A

It locks Src in its catalytically inactive “off state.”

115
Q

When Src is inactive and bound to SH2 and SH3, how can it become active?

A
  1. Removal of pTyr527 by a phosphatase
  2. Competitive binding of SH2 and SH3 by other proteins
116
Q

After Src tyrosine kinase is activated, what does it do?

A

It phosphorylates the RTK on other sites, creating more SH2 recruitment sites for other proteins in other pathways to bind.

117
Q

An abnormally activated Src leads to ____.

A

cancer

118
Q

What is the function of phospholipase C-gamma?

A

Same as phospholipase C-beta

Cleaves PIP2 to make two secondary messengers (Diacylglycerol and IP3), allowing RTks to increase cytoplasmic Ca2+ and activate protein kinase C.

119
Q

What are the major differences between phospholipase C-gamma and phospholipase C-beta?

A

Differences are in the binding domains in the C-terminus

PLC-gamma has tyrosine residues phosphorylated by the activated RTK

120
Q

What are mitogens?

A

Signaling molecules that induce cell proliferation by triggering mitosis

121
Q

Describe the signaling pathway from RTK to Ras

A
  1. Grb2 adaptor protein recognizes a phosphorylated tyrosine on the RTK via its SH2 domain
  2. Grb2 recruits Sos via its two SH3 domains
  3. Sos stimulates guanine nucleotide exchange, activating Ras (Requires GTP)
122
Q

What is the function of Sos?

A

It’s recruited by Grb2 and catalyzes the exchange of GTP for GDP in Ras

123
Q

What are Ras proteins?

A

Small/monomeric G proteins that function as binary switches

124
Q

How do GTPase activating proteins (GAPs) affect Ras?

A

They reduce Ras activation by increasing its ability to hydrolyze GTP.

125
Q

How do guanine exchange factors (GEFs) affect Ras?

A

They accelerate Ras activation by promoting the exchange of GTP for the bound GDP.

126
Q

Why is it important that Ras is turned off?

A

Oncogenic forms of Ras have mutations that interfere with its ability to interact with Ras-GAP, meaning it’s mostly in the active state and continuously signaling the cell to divide

127
Q

Phosphorylation of ___, ___, and ___ leads to the transcription of genes involved in cell proliferation.

A

Myc; Jun; Fos

128
Q

What are the three intermediates in the MAP kinase cascade?

A

Raf, Mek, Erk

129
Q

What two peptide hormones maintain blood glucose homeostasis?

A

Insulin and glucagon

130
Q

When and where is insulin produced? What does it trigger?

A

It’s produced by beta-cells in the pancreas in response to high blood glucose levels.

It triggers glucose uptake and glycogenesis.

131
Q

When and where is glucagon produced? What does it trigger?

A

It’s produced by the pancreas in reponse to low blood glucose levels.

It triggers glycogenolysis (breakdown of glycogen to glucose).

132
Q

How is insulin produced?

A
  1. Preproinsulin is translated and sent into the rough ER
  2. Clevage of signal peptide and introduction of 3 disulfide bonds makes proinsulin
  3. In the Golgi, cleavage by an endopeptidase and exoprotease makes insulin
133
Q

Insulin is stored as a _____, but released to the blood as a _____.

A

hexamer; monomer

134
Q

Insulin is anabolic. What does this mean?

A

Insulin signals the building of macromolecules, cells, and tissues

135
Q

How is the insulin receptor different from most RTKs?

A

It’s a “dimer” prior to insulin binding

136
Q

Describe the structure of an insulin receptor.

A
  1. Heterotetrameric protein
  2. External alpha-subunit linked to internal beta-subunit by disulfide bond
  3. Two of these monomers are linked by disulfide bonds so that the receptor is already dimeric without insulin
137
Q

How does the structure of insulin receptors change before and after binding insulin?

A

Unbound: Beta-subunits are too far apart to cross-phosphorylate each other

Bound: Conformational changes in the extracellular domains bring the kinase domains closer together

138
Q

What do insulin receptors bind?

A

Insulin, insulin-like growth factor I (IGF-I), and IGF II

139
Q

How does insulin receptor substrate 1 (IRS1) interact with the insulin receptor?

A

IRS1 binds to the phosphotyrosine, and the kinase on the receptor further phosphorylates multiple tyrosine residues in IRS1

140
Q

The Pleckstrin homology (PH) domain on IRS1 bind to what?

A

Phosphotidylinositols (PIP3)

141
Q

How is insulin receptor substrate (IRS) recruited to the insulin receptor?

A

IRS is recruited by its PTB domain to the phosphotyrosines on IR.

142
Q

What do adaptor proteins do?

A

They link proteins together through protein binding domains (Ex. SH3) to make larger signaling complexes

143
Q

What are docking proteins?

A

Proteins that contain:
1. An N-terminal motif/domain for direct membrane association
2. Many tyrosine phosphorylation sites for effector recruitment

144
Q

What do scaffolding proteins do?

A

They interact with multiple members of a signaling pathway and tether them into a signaling complex

145
Q

The phosphatidylinositide 3-kinase (PI3K) pathway is key to what?

A

Cellular growth and survival

This pathway is one of the most commonly altered in human tumors

146
Q

What is the difference between IP3 and PIP3?

A

IP3 stimulates release of Ca2+ from ER

PIP3 recruits proteins to the membrane

147
Q

What does PI 3-kinase convert?

A

It converts the membrane phospholipid PIP2 to PIP3

148
Q

What is the function of PIP3?

A

PIP3 serves as a docking site for proteins with PH domains

149
Q

How is Akt (protein kinase B) activated?

A
  1. Recruitment to plasma membrane via PIP3
  2. Phosphorylation by protein kinase PDK1
150
Q

After activation, what does Akt do?

A

It phosphorylates downstream proteins on ser/thr

151
Q

What is the overall effect of Akt?

A
  1. Stimulates glucose transport, glycolysis, and glycogen synthesis
  2. Stimulates cell proliferation
  3. Stimulates protein synthesis
  4. Inhibits apoptosis
152
Q

What is PTEN, and what is its function?

A

It’s a lipid phosphatase that dephosphorylates PIP3 to yield PIP2.

It’s a tumor suppressor.

153
Q

Name the six steps of the PI 3-kinase pathway.

A
  1. Growth factor or insulin binds to an RTK and activates PI 3-kinase
  2. PI 3-kinase phosphorylates, converting PIP2 into PIP3
  3. PIP3 serves as a recognition site for PDK1 and other kinases with PH domains like Akt

4 . PDK1 phosphorylates Akt when it’s docked at the membrane, activating it

  1. Akt phosphorylates many other proteins
  2. PTEN dephosphorylates PIP3, inactivating the pathway
154
Q

What is the function of rapamycin?

A

It functions like an adaptor, bringing a mechanistic target of rapamycin (mTOR) close to FKBP-12, which inhibits its kinase activity.

155
Q

What are the differences between mTOR C1 and mTOR C2?

A

mTOR C1:
1. Complexed with Raptor
2. Sensitive to rapamycin
3. Regulated indirectly by Akt
4. Stimulates cell growth and protein synthesis

mTOR C2:
1. Complexed with Rictor
2. Insensitive to rapamycin
3. Regulates Akt by serine phosphorylation
4. Regulates cytoskeleton and cell metabolism

156
Q

What is Bad? How is it inihibited?

A

Bad is a pro-apoptotic protein.

It’s phosphorylated and inhibited by Akt (Prevents the initiation of apoptosis)

157
Q

What are cytokines?

A

Small proteins that act as signaling (endocrine, paracrine, or autocrine) molecules used in immune response

158
Q

Describe the structure of cytokine receptors.

A

They transverse the membrane once, function as dimers, and are closely linke to intracellular tyrosine kinases

159
Q

Activated cytokine receptors activate what pathway?

A

JAK-STAT pathway

160
Q

What does STAT stand for?

A

Signal transducer and activator of transcription

161
Q

What are the five steps in the Jak/STAT pathway?

A
  1. When inactive, STATs are in the cytosol as monomers
  2. STATs are recruited via their SH2 domains to the phosphorylated cytokine receptor
  3. A Jak phosphorylates the STAT, causing it to come off of the receptor.
  4. The SH2 domain on STAT recognizes the phosphotyrosine on another STAT, and they dimerize
  5. Dimerization of STAT leads to its nuclear localization, DNA binding, and regulation of transcription
162
Q

Signaling through the TGF-beta superfamily requires __ types of receptors.

A

2

(Type I and type II receptors)

163
Q

Type I and type II TGF-beta receptors are always present as ______, which come together to form _______.

A

homodimers; heterotetramers

164
Q

TGF-beta receptors as composed of ___ different subunits. The receptor is a ___.

A

2; tetramer (2 Type I and 2 type II)

165
Q

How does the TGF-beta receptor complex form?

A

Type II receptor dimer binds to ligand first and then forms a complex with the type I receptor dimer

166
Q

After ligand binding, how does the TGF-beta receptor activate its activity?

A

Type II subunit phosphorylates a site on the type I subunit to activate its kinase activity

167
Q

What does the type I subunit in the TGF-beta receptor do upon activation?

A

It phosphorylates latent transcription factors AKA Smads

168
Q

What is the function of SARA?

A

It’s a scaffolding protein that binds to PI(3)P in the membrane, stimulating the phosphorylation of SMAD2/3

169
Q

What happens when TGF-beta receptors are internalized via the clathrin-mediated pathway?

A

Activation is promoted

170
Q

What happens when TGF-beta receptors are internalized via the caveolin-mediated pathway?

A

Endosomes are enriched in SMAD7, which recruits SMURF to ubiquitinate the receptor, leading to degradation.

171
Q

Does TGF-beta promote or suppress tumor formation?

A

Depends.

Normally, it’s a tumor suppressor. As tumors start spreading, they become TGF-beta resistant. In tumors, TGF-beta is oncogenic.

172
Q

What are ANPs?

A

Hormones secreted by the heart in response to high blood pressure

173
Q

What is the function of ANPs?

A

They relax smooth muscle cells in blood vessels and stimulate the excretion of Na+ and H2O.

They regulate salt and water balance, and thus blood pressure.

174
Q

Describe the structure of ANP receptors.

A

They have a kinase homology domain (KHD) and a guanylyl cyclase domain on the cytosolic side of the membrane

175
Q

How does the kinase homology domain work?

A

Upon ANP binding, conformational change leads to ATP binding and activation of the guanylyl cyclase domain

Dephosphorylation leads to desensitization

176
Q

Receptor guanylyl cyclases make ___, which activates ___.

A

cGMP; PKG

177
Q

What is the effect of activating PKG?

A

It inhibits the ER IP3-gated Ca2+ channel by phosphorylating it.

Less Ca2+, less smooth muscle contraction (Smooth muscle relaxation)

178
Q

What is nitric oxide (NO)?

A

A highly reactive and toxic, free radical gas with a short half-life (5 sec)

179
Q

What is the function of NO?

A

It functions as a signal molecule when at low concentrations.

It functions as a killer at high concentrations.

180
Q

NO is synthesized in cells by what?

A

Nitric oxide synthases (NOS)

181
Q

Name the three types of NOS.

A
  1. Neuronal constitutive NOS (nNOS)
  2. Endothelial constitutive NOS (eNOS)
  3. Induced NOS (iNOS)
182
Q

Where does nNOS function?

A

Nervous system

183
Q

Where does eNOS function?

A

Vascular system

184
Q

What is the function of iNOS?

A

Kills microbes, viruses, and surrounding cell

185
Q

What is the pathway of NO signaling in vasodilation? (6 steps)

A
  1. Acetylcholine binds to GPCR on endothelial cells, activating Gq
  2. Ca2+/calmodulin binds eNOS to activate it, leading to NO synthesis
  3. NO acts as a paracrine mediator to influence nearby cells
  4. NO binds to intracellular guanylyl cyclase and activates it, making cGMP
  5. cGMP activates PKG
  6. PKG phosphorylates IP3-gated calcium channel, inhibiting it and relaxing the smooth muscle
186
Q

What are the subunits of guanylyl cyclase?

A
  1. Regulartory (Heme containing)
  2. Catalytic (Heterodimer)
187
Q

Transport via ion channels is always [active/passive].

A

passive (In the direction of the concentration gradient)

188
Q

How do voltage-gated channels work?

A

They respond to a voltage change across the membrane

189
Q

What do ligand-gated extracellular ligand channels bind to?

A

Neurotransmitters

190
Q

What do ligand-gated intracellular ligand channels bind to?

A

Ions, second messengers, nucleotides

191
Q

How do mechanically-gated channels work?

A

They’re linked to the cytoskeleton and respond to mechanical stress

192
Q

Signaling across synaptic junctions is controlled by what kind of channels?

A

Ligand-gated

193
Q

Acetylcholine binds to which two classes of receptors?

A
  1. GPCRs to activate Gi or Gq (Muscarinic acetylcholine receptors)
  2. Ion channels (Nicotinic acetylcholine receptors)
194
Q

Describe the structure of the nicotinic acetylcholine receptor.

A

Five subunits (transmembrane alpha helix) form a channel

195
Q

How does the nicotinic acetylcholine receptor work?

A

The channel opens when two molecules of acetylcholine bind to the extracellular surface of the receptor

The pore opens, allowing Na+ to move across the membrane

Acetylcholine is rapidly degraded or removed, and the channel closes

196
Q

With acetylcholine bound, the nicotinic acetylcholine receptor stays open. True or false?

A

False. The receptor flickers between open and closed states until acetylcholine is degraded or removed.

197
Q

Steroid receptors are ____ receptors.

A

nuclear

198
Q

Nuclear receptors have [short/long]-term effects on the body. Why?

A

long

The ligands have long half-lives.

199
Q

Steroid hormones are terpenoid compounds derived from _____.

A

cholesterol

200
Q

List the five steps in which steroid hormones are derived from cholesterol.

A
  1. Isoprene building blocks (5C)
  2. Squalene (30C)
  3. Cholesterol (27C)
  4. Androgens
  5. Estrogens
201
Q

Testosterone is converted to estradiol via which molecule?

A

Aromatase (Androgens to estrogens)

202
Q

Steroid hormones enter the cell via [active/passive] diffusion.

A

passive

203
Q

Ligands for type I nuclear receptors bind with [low/high] specificity and [low/high] affinity.

A

high; high

204
Q

Type II nueclear receptors bind many compounds with [low/high] affinity and [low/high] specificity.

A

low; low

205
Q

What are selective receptor modulators (SRMs)?

A

Ligands for specific nuclear receptors (Tissue-specific regulators)

206
Q

What are the two types of SRMs?

A

SERMs: Selective ER modulators (Birth control agonist, chemotherapy)

SARMs: Selective AR modulators (Steroid abuse agonist, chemotherapy)

207
Q

What is the difference between type I and type II nuclear receptors in terms of binding?

A

Type I bind to inverted repeats as homodimers.

Type II bind to direct repeats as heterodimers with RXR (Retenoid X receptor)

208
Q

How many nuclear receptors are there in humans?

A

48

209
Q

How to nuclear receptors bind to DNA?

A

Via zinc fingers

Alpha helix of zinc fingers insert into major groove of DNA to make sequence-specific contacts

210
Q

What are enhancers?

A

Short segments of DNA that bind transcription factors that activate genes

211
Q

Nuclear receptors typically bind to what?

A

Short sequences of DNA (Hormone response elements; HREs) that function as enhancers

212
Q

Respone elements for steroid receptors are ______.

A

palindromes (inverted repeats)

213
Q

DNA binding sites for type II RXR heterodimeric receptors are [inverted/direct] repeats.

A

direct

214
Q

What are the three steps in signaling through the steroid (type I) nuclear receptor?

A
  1. Inactive receptor in the cytoplasm is bound to heat shock protein complex
  2. Binding to hormone causes receptor to dissociate from HSP
  3. Receptor dimer translocates to nucleus to bind to HREs, increasing gene transcription
215
Q

Nuclear receptors for non-steroid hormones bind to DNA as _______.

A

heterodimers (One being RXR)

216
Q

What happens when type II nuclear receptors bind to DNA?

A

They bind in a co-repressor complex in the absense of ligand, silencing the gene

217
Q

Nuclear receptors regulate gene transcription directly or indirectly?

A

Both directly and indirectly

218
Q

What are latent transcription factors?

A

Proteins that go into the nucleus to activate gene expression only after they’ve been activated

219
Q

What’s a zymogen?

A

A protein that’s produced in an inactive state and needs to be activated by protease degradation

220
Q

Wnt signaling leads to what?

A

Dephosphorylation of the protein to be degraded

221
Q

NF-kappaB signaling leads to what?

A

Phosphorylation of the protein to be degraded

222
Q

What are Wnts?

A

Ligands that act as paracrine mediators to control development and contribute to cancer formation

223
Q

What do Wnt ligands bind to?

A

Frizzled receptors

224
Q

Describe the structure of Frizzled receptors.

A

They transverse the membrane 7 times and resemble GPCRs

225
Q

Activation of Frizzled involves which co-receptor?

A

LRP (LDL-receptor-related protein)

226
Q

What is the function of the Wnt pathway?

A

Regulates the proteolysis of beta-catenin, which functions in cell adhesion and gene regulation

227
Q

When inactive, beta-catenin is in the cytoplasm in a “degradation” complex with which four other proteins?

A
  1. Axin: Scaffold protein
  2. APC: Scaffold protein
  3. GSK3: Ser/thr kinase
  4. CK1: Ser/thr kinase
228
Q

What marks beta-catenin for degradation?

A

Phosphorylation of beta-catenin by CK1 and by GSK3

229
Q

Wnt responsive genes are kept inactive by what complex?

A

Groucho co-repressor bound to LEF1/TCF activators

230
Q

List the steps of how Wnt signaling is activated.

A
  1. Wnt ligands bring together Frizzled and LRP receptors
  2. This activates the Dishevelled (Dsh) protein
  3. Dsh recruits GSK1 and CK1 to the receptor complex
  4. LRP gets phosphorylated
  5. Axin is brought to the receptor

All this disrupts the degradation complex. Beta-catenin won’t be degraded.

231
Q

Where does unphosphorylated beta-catenin go?

A

It goes to the nucleus, kicking off Groucho and binding to LEF1/TCF

Wnt target genes are transcribed

232
Q

What is Myc?

A

A transcription factor that promotes cell growth and proliferation

Target gene for beta-catenin

233
Q

What is Apc?

A

Tumor suppressor gene

234
Q

How do colonic crypts form?

A

In cells that lack Apc, beta-catenin remains high even without Wnt, leading to uncontrolled cell growth.

235
Q

What are the six hallmarks of cancer?

A
  1. Evading apoptosis
  2. Self-sufficiency in growth signals
  3. Insensitivity to anti-growth signals
  4. Sustained angiogenesis
  5. Limitless replicative potential
  6. Tissue invasion and metastasis
236
Q

Is a single abnormal cell enough cause cancer?

A

Yes

237
Q

Is a single mutation enough to cause cancer?

A

No

238
Q

Cancer increases exponentially as a function of ___.

A

age

239
Q

Cancer is usually caused by [dominant/recessive] mutations.

A

recessive

240
Q

What is the difference between dominant and recessive mutations in cancer?

A

Dominant: Gain of function enables oncogene to promote cell transformation

Recessive: Loss of function in BOTH gene copies eliminates tumor suppressor gene, promoting cell transformation

241
Q

All gain-of-mutation, dominant mutations that convert proto-oncogenes to oncogenes increase what to promote cell transformation?

A

The activity or amount of protein

242
Q

How does the p53 pathway relate to cancer?

A

It regulates reponses to stress and DNA damage

243
Q

How does the Rb pathway relate to cancer?

A

It initiates cell division

244
Q

How does the RTK/Ras/PI3K pathway relate to cancer?

A

It transmits signals for cell growth from the exterior of the cell to the nucleus

245
Q

Mutations in what protein are devastating with regard to oncogenesis?

A

p53 (Guardian of the genome)

246
Q

Mutations in TP53 are found in most cancers. Why?

A

p53 is critical. It serves as an “antenna,” altering the cell to any dangerous situations

247
Q

Most p53 mutations are in the binding domain, so p53 can still bind to DNA as a tetramer. Why does this matter?

A

Because p53 functions as a tetramer, mutation of only one allele of TP53 permits cancer

BIOC4332: Biochemistry II (7 decks)

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