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M2M Unit 3 > Week 2 > Flashcards

Week 2 Flashcards

1
Q

Nav and Kv ion channel basic structure

A

-4 membrane spanning domains

  • Kv domains are separate polypeptides
  • Nav, Cav domains are linked together as 4 repeats (I, II, III, IV) making one large polypeptide domain
  • Each domain contains 6 a-helices
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2
Q

Function of S4 helices in Kv and Nav ion channels

A

Sense voltage
4 per channel
-Positively charged residue (lys or arg) present at every third position

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3
Q

Function of S5 and S6 helices + connecting P loop

A

Form ion conducting pathway and selectivity filter

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4
Q

Principles of channel selectivity (5)

A

1) Selectivity Varies
2) Charge/Ionic Valence
3) Size
4) Dehydration
5) Multiple binding sites can increase selectivity

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5
Q

Dehydration

A
  • Ions must be dehydrated before passing through channel pore
  • Dehydrated ions are unstable
  • Ions stabilized within the pore via interactions with AA of pore
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6
Q

Kv ion channel has an _________ gate that opens when the cell is ______, and closes when the cell is _________

A

Activation gate

closed when cell is (-) - current is zero = DEACTIVATION

opened when cell is (+) - allows K+ to flow out of cell = ACTIVATION

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7
Q

Selectivity of the activation gate present in Kv and Nav depends on voltage sensing from ______ and ion conducting pathway from ______. ______ allows gate to have hinge-like motion

A

S4 helices
S5 and S6 helices

S6 segment conserved glycine

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8
Q

Nav ion channel has a ________ and ________ gate

A

Activation

Inactivation

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9
Q

Nav activation gate is _______ when cell is (-), and ______ when cell is (+)

A

closed = DEACTIVATION

open (allows Na+ to flow in) = ACTIVATION

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10
Q

Nav Inactivation gate is ______ and resting potential

A

open

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11
Q

closed Nav activation gate blocks _________, but once the activation gate opens, _________ is revealed and then ____________

A

inactivation site

receptor site inside pore

inactivation gate can swing closed = INACTIVATION

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12
Q

Inactivation gate selectivity is determined by the __________. The channel is closed when this folds over inner end of central ion-conducting pathway.

A

cytoplasmic loop connecting repeats III and IV

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13
Q

Sidedness of Ion channels means that _____________. This may require that ________ which is known as __________

A

modifying reagents have access to sites of action only from one side of the membrane

May require than channel be open = State-dependence

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14
Q

TTX

A

Illustrates Sidedness

cannot cross membrane, only binds extracellular pore entrance – not effective when intracellular

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15
Q

Lidocaine

A

Illustrates State-dependence/sidedness

Protonated form: + charge, acts intracellularly
-blocks channel only when activation and inactivation gates are open

Deprotonated form: neutral charge, can cross membrane

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16
Q

Na+, Cl-, and water leak into epithelia on _______ side (down electrochemical gradient), and ______ pump on ________ side pumps Na+ out, Cl- follows, and water follows drawn by osmotic gradient

A

apical
Na/K
basolateral

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17
Q

Apical side faces the ______, while the basolateral side faces the ________

A

lumen

interstitium

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18
Q

Another way NaCl can get across the membrane is by ____________

A

leaking across the epithelium through leaky tight junctions

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19
Q

Another way NaCl can get across the membrane is by using the ____________ cotransporter located on the ________ side of epithelium and then the leak of Cl- across on the __________ side

A

Na+/2Cl-/K+ (electroneutral) on basolateral side

apical side, drags Na+ and water with it

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20
Q

Glucose and AA absorbed into the blood by….

A

Nutrients pumped across apical membrane (Na+/AA or glucose) and then move passively out of cell on basolateral side into interstitial fluid

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21
Q

Leaky epithelia are typically present in epithelia that _____________

A

engage in massive transport of substances

small/large intestine, gall bladder, proximal kidney tubules

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22
Q

________ pumps Cl- into the cell by using energy from ______. This is on the ________ side.

A

Na/K/2Cl
Na+ leakage into the cell
basolateral side

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23
Q

The Chloride channel is located on the ______ side of the epithelium. At rest the channel is closed but when open, it allows ______________

A

apical

allows Cl-, water, electrolytes to leak out of the cell into lumen

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24
Q

Cl- channel:
Cholera –> ?
Cystic Fibrosis –> ?

A

Cholera = locks Cl- channel open, severe fluid loss

Cystic fibrosis = mutated channel, prevents epithelial secretion of serous (watery fluid)

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25
Q

_______, _______, ______, ______ are never pumped across membranes, but ALWAYS ____________

A

Water, O2, CO2, and urea

move passively down their concentration gradients

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26
Q

CO2 is a ______ substance, that is excreted by the _______. It makes up 14.5/15 moles of waste produced from each cell.

A

volatile

lungs

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27
Q

Urea is a ______ metabolic waste produce that it secreted by the ________

A

non-volatile

kidneys

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28
Q

Absorption in the GI tract is…

It plays a _______ role in excreting non-volatile metabolic wastes and regulating ECF composition

A
  • not regulated by ECF composition
  • Geared for maximum transport of nutrients at any time regardless of the needs of the ECF

MINIMAL role

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29
Q

Kidneys play a ______ role in excreting non-volatile metabolic wastes and regulating ECF composition.

A

EXTENSIVE role

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30
Q

Absorption in the kidneys

A

“I know what I like”

-Kidneys create an ultrafiltrate of plasma in glomerulus (contains water, salts, sugars, AA, and other beneficial compounds as well as non-volatile metabolic waste)

  • Plasma ultrafiltrate passes along renal tubules where all the stuff the kidneys want gets reabsorbed and waste is allowed to pass on
  • VERY energetically expensive
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31
Q

Action Potential:

1) Resting Potential

A
  • Na+ channel: activation gate closed, inactivation gate open
  • Permeability Na = 0
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32
Q

Action Potential:

2) Depolarization

A
  • Na+ channel: activation gate open, inactivation gate open
  • Maximum Na+ current during rising phase
  • Positive feedback: Na+ flowing in makes more Na+ channels open → cell depolarized (more +)
  • Once threshold is reached = all or nothing
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33
Q

Action Potential:

3) Peak

A
  • Na+ channel: inactivation gate slams shut (delayed), activation gate remains open
  • Permeability Na = 0
  • Vm is close to equilibrium potential of Na so Na+ current low
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34
Q

Action Potential:

4) Repolarization

A
  • Na+ Channel: inactivation gate

- K+ Channel: gate opens with depolarization, but is slow to open → K+ rushes out of cell

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35
Q

Action Potential:

5) Hyperpolarization

A
  • Na+ Channel: inactivation gates closed, activation gate closed (inactivation gates will start to re-open as cell returns
  • K+ Channel: cell undershoots resting potential because the K+ channel is delayed in closing
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36
Q

K+ channel acts to…

A
  • Speeds up repolarization → more AP in given time

- Negative feedback: depolarization causes K+ channels to open → repolarization → channels close

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37
Q

Intracellular concentrations of Na+ and K+ do not change much after a single AP because…

A

the number of ions that flow in and out is negligible compared to the total number of ions

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38
Q

Role of Na/K pump in AP

A

-Restores the concentrations of Na+ and K+ → Recharges the battery

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39
Q

Booster Stations:

______ acts as the energy source, while ______ acts as the detector

A

Na+

Voltage gated Na+ channel

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40
Q

Absolute refractory period

A

no stimulus, no matter how strong, can evoke another AP

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41
Q

Relative Refractory Period

A

stronger-than-normal stimulus is required to evoke another AP

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42
Q

Why is there a refractory period after each AP?

A
  • Permeability to Na+ very low, Na+ channel inactivation gates require time to reopen after repolarization
  • Permeability to K+ still high, K+ channels take time to close again
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43
Q

Accommodation of the AP

A
  • if an axon is depolarized slowly, may fail to generate an

- Axon accommodates to the slow, steady stimulus

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44
Q

Mechanism of Accommodation?

Hyperkalemia?

A
  • Slow depolarization allows time for inactivation gates of Na+ channels to close before activation channels open
  • Part of why Hyperkalemia is so dangerous! There is time for some Na+ channel inactivation gates to close
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45
Q

Threshold for AP

A

point at which Na+ flow into cell = K+ flow out of cell

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46
Q

Positive feedback nature of rising action phase in AP

A

Na+ flowing in makes more Na+ channels open = positive feedback during rising phase of the action potential

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47
Q

Safety Factor

A
  • density of Na channels in a patch of membrane required to generate enough Na current for an AP to propagate
  • We have 5-10 times the necessary number of Na+ channels
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48
Q

Benefit of having 5-10 times safety factor? (2)

A
  • Get a shorter refractory period with more Na+ channels re-opening their inactivation gates sooner
  • Need sufficient current to depolarize even when axon has branches
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49
Q

Myelin acts to increase __________ and decrease ________

A

electrical resistance between inside of axon and ECF

capacitance

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50
Q

Node of Ranvier

A

naked region without myelin

-Site where AP is propagated, where Na+ channels are

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51
Q

Saltatory Conduction

A

AP spreads from node to node

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52
Q

Small Diameter axons:

A
  • High threshold to external stimulation
  • Lower conduction velocity
  • Lower safety factor
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53
Q

Big diameter axons:

A
  • Low threshold to external stimulation
  • Fast conduction velocity
  • Higher safety factor
  • Have myelin = conduction velocity directly proportional to diameter
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54
Q

Acutre hyperkalemia occurs when ___________. This can disrupt _________

A

K+ escapes rapidly from cells, elevated extracellular K+ depolarizes cell

disrupts rhythm of heart

55
Q

CBIGK = treatment for _________

A

Ca, Bicarb, Insulin, Glucose, Kayexalate

hyperkalemia

56
Q

Ca2+ can be used as a treatment for hyperkalemia by…

A

-Ca2+ can be used to silence “Maverick” pacemakers and restore normal synchronous pattern of excitation/contraction

  • Ca2+ ions bind to fixed negative charges on outside surface of cells
  • Trick Na+ channels into thinking the membrane has been hyperpolarized → raises threshold for AP initiation
  • Stabilizes activation gates
57
Q

_____________ is the initial stage of MS, while ___________ is the final stage of MS progression

A

relapsing-remitting

Secondary progressive

58
Q

Consequences of demyelination : (3)

A

1) changes in resting potential and action potentials (harder to depolarize cell due to constant leak of K+ out of cell)
2) decreased speed of conduction in nerves (proliferation of Na+ channels along axon = more Na+ entry into cell, slowing nerve conduction)
3) MS patients must recruit more neurons to do the same function (brain reserve)

59
Q

Therapies for MS include blockers of ______ and ________. Many other therapies target __________

A

Na+ and K+ channels

immune system

60
Q

Dalfampridine

A

K+ channel blockade

Improves walking speed in patients with MS
Enhances conduction of AP in demyelinated axons through inhibition of K+ channels (prevents K+ leak and restores resting potential)

61
Q

Structure of Nuclear Pore Complex (NPC)

3 subcomplexes

A

Large macromolecule within the nuclear envelope

-made up of 30-50 distinct proteins (Nucleoporins - Nups) arranged repetitively in distinct sub complexes (Integral, Scaffold, and barrier Nups)

62
Q

Integral Nups

A

fused to form a luminal ring within the nuclear envelope, anchoring NPC in nuclear envelope

63
Q

Scaffolding layer n=Nups

A

provide framework for adding barrier layer

both cytoplasmic and nuclear filaments

64
Q

Cytoplasm scaffold filaments vs. nuclear scaffold fialments

A

Cytoplasm - free to extend into cytoplasm

Nuclear - form a basket layer that plays role in chromatin organization/gene expression

65
Q

Barrier layer Nups

A

natively unfolded proteins that line NPC channel with hydrophobic FG (phenylalanine, glycine) Nups (repeats) whose interactions form a selectivity filter

-Creates an entropic barrier or virtual gate that only certain proteins can pass through

66
Q

Types of Cargo Complexes:

A

1) Karyopherins
2) NTF2
3) NXF1/NXT1

67
Q

Karyopherins

-Receptor Family vs. Adapters

A

aka importins/exportins

Receptor family: interacts directly with cargo and FG Nups
-EX) Karyopherin Beta

Adapters: have binding sites for specific cargos and receptor family karyopherins (whole complex is transported)
EX) Karyopherin alpha

68
Q

NTF2

A

specific transporter for Ran.GDP into nucleus

69
Q

NXF1/NXT1

A

transporters of mRNA and rRNA

70
Q

Ran

A

Determines directionality of transport

71
Q

Ran.GTP interacts with _________ and promotes _________ or _________

A

Karyopherin/cargo complex

-promote dissociation (import) or stabilize complex formation (export)

72
Q

3 mechanisms for nuclear import and export

A

1) size-filtering diffusion
2) spontaneous migration
3) facilitated transport

73
Q

Size-filtering diffusion nuclear import/export

A
  • allows passage of small hydrophilic molecules (20-30kD size cut off)
  • Water, ions, small molecules
74
Q

Spontaneous Migration nuclear import/export

A
  • allows passage of amphiphilic molecules that can overcome hydrophobic barrier
  • Occurs via rapid association/dissociation from hydrophobic FG nups
  • Cannot move substances against concentration gradient
  • Includes karyopherins, B-catenin, SR-proteins
75
Q

Facilitated transport in nuclear import/export

A
  • passage of “cargo” (hydrophilic) by carriers (amphiphilic)
  • Can transport against concentration gradient
  • Requires energy coupled dissociation
76
Q

NLS (Nuclear Localization Signal) / NES (Nuclear Export Signal)

A 
NLS = transport in
NES = transport out

NLS/NES must be on cell surface

Not cleaved during transport –> Can be reused!

77
Q

Facilitated IMPORT of proteins/snRNPs through NPc:

1) Cargo + NLS bind in ______→ ____________ → brought into _________
2) Ran.GTP binds to ________ → ________________
3) __________ brought back into cytoplasm
4) Ran.GTP hydrolyzed to _______ and ____________

A

1) Cargo + NLS binds in cytoplasm → binds transporter → brought into nucleus
2) Ran.GTP binds to transporter → conformational change allows cargo to be released
3) Transporter + Ran.GTP brought back into cytoplasm
4) Ran.GTP hydrolyzed to Ran.GDP and released from transporter

78
Q

Facilitated EXPORT of proteins/snRNPs through NPC:

1) Cargo + ______ bound and Transporter + ________ bound
2) Cargo + NES binds to __________ → __________
3) ________ hydrolyzed in cytoplasm causing ___________
4) _________ spontaneously recycles back into nucleus
5) _______ special transporter binds 2 Ran.GDP molecules and _______________
6) Ran.GDP –> __________

A

1) Cargo + NES bound and Transporter + Ran.GTP bound in nucleus
2) Cargo + NES binds to transporter + Ran.GTP → transport out of nucleus
3) Ran.GTP hydrolyzed in cytoplasm separating pieces
4) Transporter spontaneously recycles back into nucleus
5) NTF2 special transporter binds 2 Ran.GDP molecules and carries them back into the nucleus
6) Ran.GDP → Ran.GTP

79
Q

Facilitated export of mRNAs through the NPC:

Coupled to __________

performed by _________ transporters

RNA is remodeled by ___________ on the cytoplasmic face

_____________ are needed to unravel nascent mRNA to allow binding of transporters

A

coupled to remodeling of RNA

  • NXF1/NXT1 transporters bind mRNA and rRNA (rate limiting step) in nucleus and transports it out into cytoplasm
  • RNA is remodeled by cytoplasmic Rnbp at cytoplasmic face
  • ATP dependent helicases needed to unravel nascent mRNA to allow binding of transporters
80
Q

4 things that regulate nuclear import and export:

A

1) Entropy (hydorphobic) barrier created by barrier Nups
2) Presence of Ran.GTP/GDP gradient
3) Interaction of cargo transporters with nucleoporins
4) composition of cargo impacts association with transport receptors

81
Q

Ran.GDP/GTP gradient controls nuclear import and export because…

A
  • High Ran.GTP in nucleus

- Hydrolysis of Ran.GTP → GDP only in cytoplasm and GDP –> GTP only in nucleus

82
Q

Cargo composition can be changed in 4 ways, impacting association with nuclear tansport receptors

A

1) Conformational change with ligand binding
2) Covalent modification of cargo molecule
3) Sequestration by binding partners (in nucleus of cytoplasm)
4) Binding/dissociation or regulatory subunits that either mask or provide signals

83
Q

3 mechanisms of protein transport

A

1) Gated Transport: between cytosol and the nucleus (Nuclear Transport)

2) Transmembrane Transport: across a membrane from the cytosol into an organelle through translocators
- EX) protein synthesis and mitochondrial import

3) Vesicular Transport: in which membrane bound transport intermediates move proteins and lipids from one compartment to another

84
Q

6 major functions of the ER

A

1) Synthesis of lipids
2) Control of cholesterol homeostasis (Cholesterol sensor and synthesis)
3) Storage of Ca2+ (Rapid uptake and release)
4) Synthesis of proteins on membrane bound ribosomes (Rough ER)
5) Co-translational folding of proteins and early posttranslational modifications
6) Quality control

85
Q

4 major functions of the golgi

A

1) Synthesis of complex sphingolpids from the ceramide backbone

2) Additional post-translational modifications of proteins/lipids
(Most notably glycosylation and sulfation)

3) Proteolytic processing
4) Sorting proteins and lipids for post-Golgi compartments

86
Q

Golgi broken up into different compartments including _____, _____, ______, and _____. In these different compartments there are ___________

A

cis (closest to ER), medial, tans, trans golgi network

different enzymes doing different functions in each area

87
Q

The tans golgi network is where ________ and ________ occurs

A
  • sulfation

- Vesicles bud from and are sorted to their correct destination

88
Q

Constitutive vesicles vs. regulated vesicles

A
  • Constitutive Vesicles: secreted right away

- Regulated Vesicles: secreted only when the proper signal is received

89
Q

Three vesicle coats

A

1) COP II
2) COPI
3) Clathrin

90
Q

COPII

A

ER to Golgi

91
Q

COPI

A

Golgi to ER

backward, allows recycling of proteins

92
Q

Clathrin

A

Trans Golgi to plasma membrane (also does endocytosis)

93
Q

Vesicular transport involves the movement of _________ via _________, ________, and __________.

Specific AA motifs on the cytosolic side of _________ are recognized by _________ for __________

A

movement of cargo and membrane proteins

  • budding of vesicles
  • fusion of some vesicles into tubules
  • fusion of vesicles/tubules with the next compartment

Membrane proteins
adaptor proteins
recruitment into vesicles

94
Q

ER signal sequence

A

On cargo proteins or transmembrane proteins

  • on newly formed polypeptide chain at N-terminus
  • directs engaged ribosome to ER membrane
95
Q

Signal Recognition Particle (SRP) structure and function

A

Structure:

  • 6 proteins + 1 RNA
  • Flexible binding pocket (can bind variety of signal sequences)

Function:
-Binds nascent polypeptide and ribosome, pausing translation until it also binds SRP receptor (on ER)

96
Q

Translocon structure and function

A

-protein channel, allows polypeptide chain to enter ER

Structure:
-3 protein complex, forms an aqueous pore that is closed unless a protein is coming through

Function:
-Allows protein to be fed from outside of ER to inside ER lumen as it is made

97
Q

6 Steps for Cargo Protein synthesis

A

1) ER signal sequence on very beginning of N-terminus of polypeptide chain
2) SRP binds signal sequence and brings it to ER
3) SRP binds SRP receptor on ER and protein begins to be fed through translocon into ER
4) signal peptidase clips off signal sequence
5) Cargo protein done getting synthesized, ribosome falls off
6) protein gets folded and sits inside ER lumen

98
Q

Type 1 Transmembrane protein

A

amino termins in ER, carboxy out

1 transmembrane domain

99
Q

Stop-Transfer signal

A
  • on mRNA, sequence recognized by translocon, translocon releases this sequence
  • The rest of the protein (C-terminal end) made in cytosol
100
Q

Type 2 Transmembrane protein

A
  • amino outside of ER, carboxy in
  • 1 transmembrane domain
  • (+) charged AA on amino side of the TMD orient amino end to the cytosol
101
Q

N-linked glycosylation occurs in the ________. It is the process of __________ that functions to __________ and __________.

A

Lumen of ER

Adding preformed carbohydrate complex to asparagine (N) to polypeptide

Function:

  • Keep proteins from aggregating when hydrophobic domains are exposed
  • Glucose on complex acts as tag to monitor unfolded proteins (determines if they are properly folded or not)
102
Q

Clinical features of Vibrio Cholerae infections: (5)

A

1) only infects humans
2) incubation 18 hours - 5 days
3) can have asymptomatic cholera (majority of people infected are asymptomatic)
4) Severe, acute, rapidly fatal watery diarrhea (non-inflammatory
5) both epidemic and pandemic

103
Q

________ is the cause of death with cholera

A

DEHYDRATION

104
Q

________ distinguishes between V. Cholerae Strains

A

> 200 serogroups based on O-Specific polysacchardie (OPS) of LPS

105
Q

___________ and _________ both protect against cholera disease infection

A

Prior immunity (recent exposure, you get less sick)

Having one mutant cystic fibrosis gene (CFTR) because cholera toxin isn’t able to constitutively opne Cl- channel

106
Q

Treatment of cholera is with ____________

A

oral rehydration fluids with glucose, which enhances sodium and electrolyte reuptake

107
Q

Two major routes for endocytosis

A

1) Phagocytosis

2) Pinocytosis

108
Q

Phagocytosis

A
  • Macrophages and neutrophils in blood
  • Recognize foreign organisms, engulf them, and deliver them to lysosomes for degradation
  • Recognize apoptotic cells
109
Q

Pinocytosis, two major routes

A

(small vesicle formation)

-Involves small volumes – specific uptake of ligands and receptors

1) Clathrin Coat Proteins
2) Caveolae

110
Q

Clathrin coat proteins

A

endocytic vesicle coat that forms on a vesicle budding from the plasma membrane

111
Q

Pinocytosis via clathrin coat protein steps:

A

1) cargo molecule binds transmembrane receptor
2) Adapter protein binds short motif on cytoplasmic domain of receptor
3) Adapter complex of proteins forms on intracellular side and clathrin coat assembles on budding vesicle
4) Dynamin pinches vesicle off membrane
5) adaptor complex and clathrin dissociate from vesicle inside cell

112
Q

Caveolae

A
  • endocytic vesicles that form without coat proteins
  • important in lipid raft regions and used by some animal viruses and cholera to enter cell
  • Made up of 114 calveolin (structural proteins)
113
Q

Quality control of protein synthesis in the ER is ensured by…

A
  • folding enzymes that recognize if a protein is folded properly via glucose tail from N-linked polyoligosaccharide
  • glucosidase II adds glucose to protein if it is improperly folded, and funneled back into system to get refolded
  • if folding is bad and can’t be fixed –> proteosome
114
Q

hsp70

A
  • Made in high abundance when cell is hear shocked

- Binds exposed hydrophobic patches in incompletely folded proteins and prevents aggregation

115
Q

hsp60

A
  • Large, barrel-shaped structure with chamber
  • Feeds misfolded proteins into chamber and helps it fold
  • uses ATP
116
Q

Ubiquination-Proteasome System (UPS)

A
  • responsible for rapid degradation of proteins when fast adaptation is needed
  • 4 molecule ubiquitin tag sends protein to proteosome
117
Q

Ubiquitin molecules

A
  • attached to proteins by E1, E2 and E3 ligase enzymes as they leave the ER –> 4 (polyubiquitins) target protein to proteosome
  • ubiquitin molecules cut off by proteosome and recycled

-mono and multiubiquitins used as regulatory signals instead of degradation signals

118
Q

Proteosome

A

huge complex of proteins, unwinds misfolded protein and feeds protein strand into a compartment that cuts the protein into short 7-9 AA peptides

-Dispersed throughout cytoplasm

119
Q

Proteosome structure:

Cap
Cylinder
Alpha Subunits
Beta Subunits

A

Cylinder: where proteolytic cleavage occurs

Cap: recognizes polyubiquitin, uses ATP to unfold protein and feed it into cylinder

Alpha subunits – regulate substrate entry into “death chamber”

Beta subunits – do actually clipping of subunits

  • B1 – cleaves after acidic AA
  • B2 – cleaves after basic AA
  • B5 – cleaves after hydrophobic AA
120
Q

Lyososome

A

-Degrade extracellular materials taken up by endocytosis and some intracellular components

  • Contain enzymes that degrade all classes of molecules – proteins, lipids and sugars
  • Transporter in lysosomal membrane allow exit of AA, monosaccarhides, nucleotides, and lipids for reutilization within cell
  • Proton pump makes lysosome lumen acidic (pH 5)
121
Q

Macroautophagy

A

-Formation of a double membrane vesicle that captures cytosolic components/organelles → fuse with lysosome → hydrolases degrade contents of autophagosome

122
Q

Function of macroautophagy

A
  • Remove/recycle organelles, proteins, and other macromolecules
  • Cell survival under stress conditions
  • Neuro-protection
  • Immune response and removal of intracellular pathogens
  • Aging – (caloric restriction increases life span)
  • Tumor suppression/promotion
  • Regulates apoptosis/cell death (promote OR inhibit)
123
Q

Chaperone-Mediated Autophagy

A
  • Recognition of specific proteins that contain a specific recognition sequence (based on AA sequence KFERQ) → direct binding and delivery to lysosome
  • Delivers specific proteins in a controlled manner to autophagosomes
124
Q

Macroautophagy Process

A

1) Activate a PI3K complex that allows nucleation of a membrane that will eventually form the autophagosome.
2) Regulation of protein conjugation events to extend membrane.
3) Randomly capture or specifically deliver cargo to the extending autophagosome, then join the membrane to close the vesicle
4) Fuse with lysosome
5) Recycle amino acids and other macromolecular precursors.

125
Q

Autophagy Protection against Neuro-degeneration

A
  • Aggregate-prone proteins (e.g. Huntington’s) will cause neuronal cell death
  • Autophagy degrades the aggregate-prone proteins → no toxic stimulus → not neuronal cell death
126
Q

Apoptosis induction and autophagy

A

-Many proteins (e.g. Bcl-2) that regulate apoptosis (cell death) also control autophagy
→ problems for interpreting therapeutic interventions designed to target these proteins

-Apoptotic proteases (capases) can cleave essential autophagy regulators → inactivate them, and block autophagy

127
Q

4 characteristics of apoptotic cells

A

1) Collapse of the nuclease, endonucleases chop up DNA between histones on linkers
2) Cell shrinks – loses 1/3 of volume in a few seconds

3) Cell tears itself apart into apoptotic bodies
• Plasma membrane still intact

4) Recognized by another cell and phagocytosed before dangerous pro-inflammatory contents spill out of cell

128
Q

In a normal cell Phasphatidylserine (PS) all on _________ (maintained by ________)

In an apoptotic cell, PS becomes ____________ (done by __________)

_________ with PS receptors recognized, bind, and ingest cells that have committed to apoptotic pathway

Removal of apoptotic cells is ______________

A

inner leaflet of cell membrane, flippase

equal on both sides of the membrane, scramblase

Macrophages

physiologically silent

129
Q

Tissues/cells with lots of apoptosis

A

Thymus – gets fully replaced every 3 days

Lymphocytes – 95-99% of lymphocytes that develop fail to be selected to mature as useful T cells

  • Most radiation-sensitive cells – low-dose radiation does not kill lymphocytes, but induces them to kill themselves
  • Die so easily because they are so dangerous due their rapid proliferation abilities

Morphogenetic death – important during development in determining the final shape of body parts and organs

130
Q

Intrinsic Apoptosis

1) Perturbation of ___________
-Normally membrane guarded by _____________ protein family member (Bcl-2 and Bcl-XL)
__________ made and replace anti-apoptotic
→ Membrane permeable to ___________

2) __________ released into cytoplasm from mitochondria
3) cyt C activates _______ in cytoplasm
4) Apaf-1 activates ________ which activates _______ (proteases)

  • Capase-9 = ?
  • Capase-3 = ?
A

1) mitochondrial outer membrane function
anti-apoptotic Bcl-2
Pro-apoptotic Bcl
cytochrome C

2) cytochrome C
3) Apaf-1
4) capase-9, capase-3

capase-9 = signal capase
capase-3 =  executioner, cleaves many substrates
131
Q

Extrinsic Apoptosis:

1) __________ up-regulates expression of __________
2) Fas L activates _________ on cell surface
3) Fas (CD95) transduces signal, activates _________
4) FADD activates _______ which activates ________

A

1) Cytotoxik (killer) T cells (CTL), Fas Ligand surface molecule
2) Fas (CD95)
3) FADD
4) capase-8, capase-3

132
Q

Continuum of response to damage

A
  • First repair
  • If repair is impossible of unwise, then apoptosis
  • If damage is overwhelming, then necrosis
133
Q

Autoimmune Lymphoproliferative Syndrome (ALPS)

A

failure of lymph cells to die

-new way of thinking about malignancy

M2M Unit 3 (3 decks)

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