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Exam 2 > Secretory Pathway > Flashcards

Secretory Pathway Flashcards

1
Q

components of endomembrane system

A

endosome, nuclear membrane (extension), lysosome, golgi, ER with ribosomes, plasma membrane

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2
Q

nuclear pores

A

proteins in, mRNA out outer nuclear membrane IS continuous with ER - fold around at nuclear pores, transcription factors in and mRNA can leave, NOT protein lined - continuity btwn cytoplasm and nucleus

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3
Q

Rough ER jobs

A

secreted and membrane protein biosynthesis steroid synthesis oxidative modification of xenobiotic COP II vesicle formation

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4
Q

Smooth ER jobs

A

generation of limiting membrane in autophagy

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5
Q

Rough and Smooth ER jobs

A

phospholopid and cholesterol synthesis Calcium storage (especially in muscles) MHC I ag presentation

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6
Q

ER client proteins

A

secreted proteins (enzymes, Igs, extracellular matrix proteins) integral membrane proteins of endomembrane system (receptors, transporters, channels, cell adhesion) lumenal proteins of endomembrane system (lysosomal hydrolyses, ER chaperones)

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7
Q

non-ER client proteins

A

made on free polysomes in cytoplasm and imported where they need to go cytosolic (cytosekeletal, contractile, soluble enzymes) peripheral membrane proteins on cytoplasmic face (spectrin) nuclear, mitochondrial, perixisomal proteins

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8
Q

translocation

A

protein synthesis on cytoplasmic side of ER membrane, nascent polypeptide is translocated through the protein lined channel into the lumen where modifications happen

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9
Q

N-linked glycosylation

A

HIV gp160 insulin receptor, addition of pre-assembled Glu3-man9-glcnac2 branched sugars to amide groups of Asparagine

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10
Q

co-translational glycosylation

A

the signal for glycosylation is linear! add glycosylation before polypeptide folds, enzymes transfer in ER lumen as translate - amino end of protein can be in the lumen or the cytosol, transferred over to reside

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11
Q

oligosaccharyl transferase

A

transfers phospholipid of sugars made in the ER by enzymes onto Asn of nascent polypeptide cytoplasm is a reducing environment, make it as the protein is folding, transfer from dolichol in membrane

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12
Q

chaperones

A

facilitate folding etc. in the Er

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13
Q

proinsulin

A

protein with 3 disulfide binds - needs chaperone to facilitate oxidation

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14
Q

BIP

A

chaperone binds to hydrophobic stretches of AAs in the ER i.e. proinsulin and glycoproteins bind to AAs, hydrolyze ATP, fall off, binds new stretches of hydrophobic AAs on peptide - if fold naturally, it won’t be right, BIP binds to prevent from folding in a way that can’t be unwound during/after synthesis

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15
Q

Calnexin-Calreticulin

A

chaperone i.e. HIV gp160 receptor binds to glucose! lectin properties released if protein loses glucose binds oligosaccharide with a terminal glucose to target it for degredation glucose usually trimmed when oligosccharide is added during N-linked glycosylation re-add glucose if misfolded so C-C binds

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16
Q

ERAD

A

ER associated degradation, to degrade misfolded or slowly folding proteins balance! if folds slowly –> more ERAD

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17
Q

ubiquitin

A

if protein is misfolded, retains chaperone, stays in ER translocated through membrane into cytoplasm (ATPase pulls it through) N-glycanase cleaves off glycoproteins ubiquitin ligase adds ubiquitin covalently to LYSINE (K) tags for degradation to proteasome (ubiquitin recycled)

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18
Q

del508 mutation

A

mutant CF gene poor folding and OFF (ERAD) is predominant way lacks channel so can’t regulate the ion concentration in the airways and can’t clear mucus

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19
Q

gain-of-function mutations

A

most misfolded proteins are loss-of-function some - lead to toxic accumulation of misfolded proteins, like Alzheimers, T2D –> toxic, ER stress –> trigger apoptosis

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20
Q

Synuclein

A

in fruit flies failure to fold is toxic - if overexpress, don’t fold, kill neurons if add chaperones –> mediate folding in the cytoplasm

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21
Q

ER stress

A

an imbalance btw capacity of the ER to process client proteins and load of proteins imposed on the organelle capacity: chaperones, oxidoreductases, glycosylation, protein degredation, lipids (membrane) demand: physio load, mutant proteins

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22
Q

ATF6, IRE1, PERK

A

tell when ER stress - when proteins not folding when activated –> turns on protein synthesis of what you need and inhibit what you don’t decreases load on ER but increase expression of genes that the ER needs rectifying response to ER stress

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23
Q

PERK

A

if making insulin - it’s all accumulating in the ER - not enough to make it and not enough capacity in ERAD! accumulate and cells die if no PERK - cells are destroyed! (ER response signal)

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24
Q

autophagy

A

alternate method to get rid of accumulated misfolding proteins in in ER ER–> under stress –> engulf part of cytoplasm with ER and contents –> merge with lysosome when not enough capacity and degrade by acid hydrolysis

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25
Q

COPII

A

ER to golgi smooth ER has exit sites with stable proteins made that turn into vesicles

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26
Q

COPI

A

golgi to ER

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27
Q

Sec23/24

A

inner coat proteins - binds to cytoplasmic tails of seected membrane proteins

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28
Q

Sec13/31

A

outercoat - able to deform membrane as binds and proteins old - area the COPII vesicles will form

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29
Q

ERGIC

A

clotting factors in vesicles - hemophilia if not secreted correctly

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30
Q

KDEL

A

COPI vesicles on things that need to cycle back from cis golgi to ER (chaperones have) These proteins are not free to diffuse into areas of COP II vesicles and if escape, brought back target sequence on peptides that need to stay in the ER, will be retrieved from golgi if there KDEL receptors have KKXX on receptor in COPI vesicle retrieves BIP from CGN

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31
Q

modification of core oligosaccharides in golgi apparatus

A
  1. oligosaccharide is added to Asn residue in the ER
  2. in the ER - glucosidase I and II removes 3 glucose, ER mannosidase removes 1 mannose, moves to golgi lumen
  3. in golgi - golgi mannosidase I removes 3 mannose - high mannose oligosaccharide!
  4. N-acetylglucosamine transferase I adds GlcNAc
  5. golgi mannosidase II removes 2 mannose
  6. add NANA (sialic acid) Gal, GlcNAc - very negatively charged! complex oligosaccaride
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32
Q

0-glycosylation

A

side chains built in golgi! can occur on lipids and proteins

on proteins: ser/thr - hydroxyl group

can add A and B group on proteins for antigens

enzymes in cisternae of proteins

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33
Q

CGN

A

sorting!

phosphorylation of oligosaccarides on lysosomal proteins

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34
Q

cis cisterna

A

removal of Man

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35
Q

medial cisterna

A

removal of Man

addition of GlcNAc

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36
Q

trans cisterna

A

addition of Gal

addition of NANA

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37
Q

TGN

A

sulfation of tyrosines and carbohdrates

sorting!

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38
Q

Furin

A

in TGN

catalyzes cleavage and activation of many proteins

removes sections to activate the proteins

i. e. HIVGP-160: only active when cleaved! Furin cleaves at certain basic AA
i. e. insuli receptor - cleaves it to activate it

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39
Q

transport of soluble lysosomal enzymes

A

TGN –> endosomes

protein from ER: add p-GlcNAc in CGN (phosphotransferase) –> cleave sugar and leave phosphate mannose –> uncovers M6P signal –> TGN –> bind to M6PR –> recruits clatharin coat –> transport vesicle –> fuse with early endosome –> dissassociate at low pH –> remove phosphate –> retromer coat to bring back

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40
Q

maturation of secretory vesicles

A
  1. proteins leave TGN
  2. acidic - aggregates
  3. membrane pinches off
  4. more acidic –> more aggregated –> remove membrane
  5. mature
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41
Q

PC

A

prohormone congertase

for all peptide hormones produced in this fashion

in immature secretory vesicles –> decrease pH for aggregating –> cleave proinsulin to insulin

cleavage of prohormone precursors in immature granules

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42
Q

how are vesicles targeted?

A
  1. microtubules! cytoskeleton can direct vesicles to their target membranes using microtubule based motor proteins that specifically bind to different vesicular carriers
  2. docking proteins control initial binding of vesicles to their target membranes
  3. SNARE proteins - specificity!
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43
Q

what cells traffic with microtubules?

A
  1. fibroblasts
  2. neurons

dyenin - goes in one direction, recruits different MT motors

44
Q

Rab proteins

A

Rab-GTP is on vesicles

RAB-GTPase regulates docking! long protein on target, when there is membrane fusion, GTP is hydrolyzed.

each vesicle needs a specific Rab protein to know where it goes

45
Q

GEF

A

guanine-nucleotide exchange factor

on donor compartment, exchanges GDP for GTP on rab for a new vesicle

46
Q

VAMPS

A

V-Snares - only fuse w right t-snare

on vesicle

47
Q

STX

A

T-snares - target snares! only fuse w right v-snare

recruit cargo

48
Q

Mast cells

A

in connective tissues

if increase Ca2+ –> synaptic vesicles dock and fuse –> unregulated! asthma and allergies

49
Q

neuron synapse

A

action potential - increase in ca 2+ -snare proteins fuse - secretory granules

50
Q

Synaptotagmin

A

on vesicles - binds Ca2+ and regulates SNARE complex

Ca2+ binding in synaptic vesicles binds V-snares and prevents fusion - when Ca2+ releases V and helps the complex form

on vesicle!! inserted into membrane when bound to Ca2+, pulls plasma membrane up under the vesicle so there is easier fusion

51
Q

Botox for migraines

A

relaxes muscles in head - inhibit synaptic transmission 0 cleaves snares so no vesicle fusion

52
Q

phagocytosis

A

cell eating

53
Q

pinocytosis

A

cells drinking - small particles, gulp large volume

54
Q

clathrin triskeleton

A

3 clathrin heavy chains, 3 clathrin light chains

spontaneously form “cage” in cytosol

55
Q

adaptor proteins

A

4 diff polypeptides - heterotrameric

bind clathrin and associate with membrane - bring clathrin to the membrane

membrane binding domain, binds to cargo (core)

clathrin binding domain (hinge)

accessory protein binding (appendage)

56
Q

AP2

A

core plasma membrane adaptor for clathrin

rec specfic linear signal XXXL, YXX

mu2 subunit and alpha/sigma 2 subunits recognize

57
Q

AP1

A

core plasma membrane adaptor for clathrin on TGN and endosomes

58
Q

Dynamin

A

assembles into a ring around neck of forming bud - recruits other accessory proteins which destabilize lipid bilayer and vesicle pinches off

recruits GTPase - squeeze - provides E for the fusion of membranes and pinches

mutations in dynamin - deeply invaginated that can’t detach

59
Q

sorting/early endosomes

A

pH about 6

ligand and receptor dissassociate

receptor in tubule, will be recycled

ligand will be degraded

60
Q

pways of endosome/lysosome system

A
61
Q

LDL

A

constituitive endocytosis!

LDL binds cholesterol, binds LDLR, endocytosed (clatharin)

sorting endosome - (low pH), LDL falls off of LDLR, lysosome, degrade LDL and recycle receptor

in lysosome - NPC1 and 2 - bind cholesterol and exit from digestive enorganelles

LDL - when cell needs cholesterol - put LDLR into PM

LDLR associates with clatharin coated pits

62
Q

transferrin

A

constituitive endocytosis!

iron

nutrient uptake

temporally regulated

Fe3+ binds to transferrin - endocytosed (clathrin) –> endosome –> change conf and release Fe - high affinity for receptor and recycle back to surface

Apo-tranferrin (no iron) into liposome

63
Q

NPC1 and 2

A

takes cholesterol out of lysosome

64
Q

Familial hypercholeterolemia

A

increased LDL in bloodstream

devective LDL internalization

65
Q

autosomal recessive hypercholesterolemia

A

defective adaptor protein - receptors are fine but adaptors are not

66
Q

PCSK9

A

protein secreted by hepatocyte to regulate surface expression of LDLR

when endocytosed - degrade LDLR in the lysosome with LDL

can’t be recycled!

treatment: antibodies for PCSK9 - not there, can’t decrease LDLR -

67
Q

EGF

A

ligand induced signal transduction

cytoplasmic downregulation of receptor tyrosine kinases - only when ligand binds to R

EGFR is regulated by ubiquitin and ESCRTs - cancer if not downreg

68
Q

ubiquitin

A

ligases - tail added to R before it’s endocytosed to prevent it from entering the tubules - invaginating body pinches off and brings into lumen so isolated from cytosol

merge w lysosomal protease/lipase,

cleave

69
Q

ESCRT

A

proteins that recognize ubiquitylated membrane proteins and sort into internal vesicles of multivesciular body

ESCRT -0,1,2,3, - bend endosomal membrane to form lumen - how downregulate membrane protens

70
Q

GLUT4

A

Glucose transporter - major insulin regulator in muscle/adipose

stored in recycling endosomes and translocates in respose to insulin to increase glucose intake

T2D - insulin but no response!

71
Q

Zipper mechanism

A

mechanism used by bacteria to induce phagocytosis by nonphagocytic host cells

bacteria expresses adhesion protein that binds w high affinity to a protein that usually binds to another cell (integrins, cadherins) i.e. adhesin bind to cadherin on host cell

form cell junction - move actin into cell etc, phagocytose

72
Q

trigger mechanism

A

bacteria injects effector molecule into host that activates Rho-family GTPases –> actin polymerization –> ruffle etc. –> throw up large actin protrusions –> trap

73
Q

anthrax

A

B subunit binds to receptor - cleaved - large subunit remains bound to R

7 B complexes form ring on target cell

Subunit A binds to the ring - endycytosed - in early –> late endosomes

decreased pH in endosome - ring conf change - pore in membrane - A enters cytosol

74
Q

Ebola

A

ebola bnds - endocytosed –> early/late endosomes –> host cysteine proteases cleave GP and remove mucin and glycan cap - expose NPC1 binding domain

cleaved GP binds to NPC1 domain on lysosome compartment

triggers - conf change - viral membrane fusion and release in cytoplasm

75
Q

LIMPS

A

highly glycosylated proteins on the lysosome - so the hydrolases won’t break down lysossome protein - sugar layer

lysosomal integral membrane proteins are highly glycosylated

76
Q

hydrogen pump

A

ATP driven - maintains acidity with ATP

77
Q

M6P

A

marker on all newly synthesized lysosomal hydrolases

N-linked oligosaccharide - put M6P on it!

78
Q

GlcNAc phosphotransferase

A

in golgi

lysosomal hydrolase was was N-glycosolated in ER on Asp residue

adds UDO-GlcNAc to lysosomal hydrolase in the golgi

recognizes signal patch of lysosomal hydrolase and attach GlcNAc-P to mannose in oligosaccaride –> removes GlcNAc so only P remaining (uncovering of M-6-P signal)

79
Q

M6PR

A

after M-6-P signal uncovered - binds to M6PR in trans golgi network - clatharin coated vesicle - merge w endosomes and dissasociate from R bc low pH

phosphotase removes phosphate (marker)

M6PR go back to TGN in retromer vesicle

80
Q

MPR300

A

major transmembrane glycoprotein w 2 M6P bind sites and bind site for IGFII at repeat 11

bring hydrolases with M6P

81
Q

LIMP-2

A

lysosomal integral membrane protein - heavily N-glycoslyated

trafficking in M6P in independent manor

1 way - doesn’t return

binds beta-GC from TGN to lysosome

82
Q

Tay Sachs

A

mutations in genes that encode catabolic enzymes involved in the degredation of macromolecules

deficiency of Hex A activity caused by HexA gene encoding alpha subunit

Hex B activity is normal or increased

83
Q

MPR46

A

minor MP6PR - only 1 bind site, dimer for increased affinity

non covalent dimers

bring hydrolases with M6P

84
Q

sortillin

A

transport receptor for NP, Type I transmembrane, bring things to lysosomes

85
Q

I-cell disease

A

defects in post-translational processing of lysosomal enzymes

errors in enzyme traficking/targeting

86
Q

NPC disease

A

defective function of non-enzymatic lysosomal transmembrane and soluble proteins (transport of cholesterol out of lysosomes)

87
Q

GM2 ganglioside

A

ganglioside with sialic acid, storage material in the brain

88
Q

HexA

A

to break down Gm2 - cleaves it in the lysosome

alpha and beta subunits with Gm2 activator protein

Need Hex A and Hex B to break down Gm2 ganglioside

glycolipid bind site - lifts and extracts GM2 (ganglioside) from membrane - forms complex and hydrolyzes

89
Q

beta-hexosaminidase system

A

need 2 polypeptides - alpha and beta and GM2 activator protein

90
Q

Sandhoff

A

deficiency of Hex A and Hex B activities by mutations in HexB gene that encode beta subunit common to HexA and HexB

91
Q

AB variant

A

mutations of MG2A gene encoding Gm2 activator protein - Hex A and Hex B ativities are normal but no hydrolysis of Gm2

92
Q

ML II/III

A

lysosomal disorder

deficiencey of GalNac-PT - enzyme in golgi that gives M6P marker to hydrolases

hydrolases don’t reach destination - undigested material in lysosomes

93
Q

MSD

A

defect in post translational modification

genetic deficiency of FGE that oxidizes suflatases and makes them active

no sulfatases

94
Q

NPCI

A

defect - loss of protein - can’t redistribute LDL-derived cholesterol from lysosome to ER and PM

95
Q

metabolic cross-correction

A

addition of M6P - transport to lysosome

recaptured by same/neighboring via cell surface M6PR –> endocytosis –> lysosome

take up exogenous enzykme –> deliver to lysosome –> degrade stored substrate and restore homeostasis

infuze enzyme outside body and infuse through stem therapy, gene therapy, enzyme

NOT every cell needs to be corrected - small amt makes big diff

96
Q

substrate reduction therapy

A

lysosomes - drug that inhibits first step in glycosphingolipid biosynthesis, decrease rate of making to offset issues with breakdown

possible to cross blood brain barrier

97
Q

pharmacological chaperone therapy

A

incrase folding/prevent premature degredation of defective lysosome enzyme

correct folding and decrese degredation in ER so gets to lysosome

even tiny percent increase is ok!

98
Q

autophagy

A

self eating - ubiquitous proess in eukaryotic cells that results in breakdown of cytoplasm within lysosome in response to stress or to change

engulf organelles and merge w lysosome

99
Q

macroautophagy

A

most common form of autophagy

phagophore/limiting membrane –> autophagosome –> autolysosome

100
Q

chaperone mediated autophagy

A

Hsc70 binds to substrate protein in cytosol and thread through membrane of the lysosome

101
Q

microautophagy

A

trapped in lysosome by invagination - usually non selected

102
Q

lysosomal exocytosis

A

Ca2+ enters cell –> lysosomes triggered to excrete contents and repair PM

103
Q

CLEAR gene network

A

lysosomal proteins - coexpressed and regulated by TFEB

regulates lysosomal biogenesis and function

104
Q

TFEB

A

transcriptonal factor that promotes lysosomal biogenesis

mTORC1 - controls cell growth in response to nutrients and growth factor

if adequate lysosomal function: mTOR (on lysosome) phosphorylates TFEB, triggers the binding of 14-3-3 protein to TFEB - keep TFEB in the cytoplasm –> no translation!

if inhibition of lysosomal function: decrease mtor - dephosphorylation of TFEB, no binding of 14-3-3, TFEB can ener nucleus and stimulate lysosomal genes

i.e. if not enough AA - TFEB works to turn on genes, degrade more proteins and make more AA

105
Q

LYNUS

A

lysosomal nutrient sensing - on surface of lysosome

regulate proteins assosicated with mTOR

LYNS - includes ATPase and all involved with mTOR

if enough nutrients: TFEB binds w LYNUS - sense lysosomal nutrient level and phosphorylates TFEB to sequester it

if starvation - mTOR is released from LYNUS, inactive! can’t phosphorylate - TFEB enters nucleus and turns on more genes (including itself! autoregulatory loop for more degredation)

Exam 2 (8 decks)

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