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MIMS > Membrane Dynamics and Function > Flashcards

Membrane Dynamics and Function Flashcards

1
Q

what are the 4 general ways substances can be exchanged across the PM?

A

lipophilic substances dissolve in PM, channels allow materials to diffuse through, transporters couple transport to energy source to move materials against concentration gradient, in eukaryotes vesicles used to import and export materials

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2
Q

why are lipophilic chemical signals made on demand?

A

cells can’t retain them as they can dissolve in and pass through membranes

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3
Q

how are non-lipophilic messengers recognised by cells?

A

bind to either extracellular binding site on a channel or on an allosteric membrane-spanning protein

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4
Q

describe the nucleus

A

home to genome, separated from cytosol by double membrane penetrated by complex nuclear pores (perhaps 4000/nucleus) through which materials guided in and out

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5
Q

describe the endoplasmic reticulum

A

most abundant and invasive organelle, makes contact with most other organelles in cell, encloses ER lumen where proteins mature and Ca2+ stored

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6
Q

what does the RER have that the SER doesn’t?

A

studded with ribosomes (site of protein synthesis)

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7
Q

role of ER?

A

lipid synthesis, steroid synthesis, protein maturation, Ca2+ storage, RER= protein synthesis

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8
Q

describe the Golgi apparatus + its roles

A

stacks of tubules linked to ER by vesicular trafficking. important roles in maturation/glycosylation of proteins + their dispatch to other intracellular destinations

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9
Q

how many mitochondrial genes are there? what do they do?

A
  1. encode tiny fraction of mitochondrial proteins. are transcribed and translated within mitochondria using machinery reminiscent of bacteria.
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10
Q

how are proteins dispatched to different locations after forming on a cytosolic ribosome?

A

address labels within primary sequence dispatch proteins to different destinations

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11
Q

what causes fully folded proteins to move to the nucleoplasm through nuclear pores?

A

nuclear localisation signals

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12
Q

why do all proteins that don’t go to the nucleus have to remain partially unfolded before reaching their final destinations?

A

the rest all have to cross a membrane to reach their final destinations, need to be partially unfolded to be threaded through protein pore within target membrane

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13
Q

state of proteins destined for mitochondria and peroxisomes before being dispatched from ribosome?

A

fully translated

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14
Q

what is co-translational targeting, what destination usually has proteins that use co-translational targeting?

A

when the protein is dispatched before translation is complete. proteins destined for ER usually use this

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15
Q

what is the nuclear localisation signal?

A

stretch of around 6 positively charged residues anywhere in primary sequence of proteins, recognised by importin, directs reversible passage through nuclear pores

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16
Q

address label for proteins destined for peroxisomes?

A

C-terminal sequence SKL-e recognised by PTS1 receptor

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17
Q

what causes Zellweger syndrome?

A

non-functional PTS1 receptor for proteins targeted to peroxisomes

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18
Q

what are the 4 destinations in the mitochondria for proteins?

A

inner and outer membranes, inter-membrane space, matrix

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19
Q

what is the address label for proteins destined for the mitochondrial matrix?

A

N terminal amphipathic helix recognised by a chaperone protein

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20
Q

is targeting to peroxisomes and mitochondria reversible or irreversible?

A

irreversible

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21
Q

where can proteins sent to the ER be sent to from there?

A

Golgi, lysosomes, secretory pathway, plasma membrane

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22
Q

signal sequence for proteins sent to the ER lumen vs ER membrane?

A

hydrophobic signal sequence (at least 8 continuous hydrophobic residues) at the N terminal for ER lumen proteins, internally for integral membrane proteins. recognised by the SRP

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23
Q

what is the SRP?

A

signal recognition particle- a large protein-RNA complex which recognises the hydrophobic signal sequence of proteins sent to the ER

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24
Q

what happens when the SRP detects the hydrophobic signal sequence on an incompletely translated protein?

A

translation arrests, SRP-nascent peptide chain associates with SRP receptor on ER membrane. SRP receptor associates with translocon (protein channel in ER membrane), checks signal sequence of peptide. nascent peptide chain inserted in appropriate orientation into translocon (this is final orientation). SRP is released

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25
Q

what happens when the SRP releases the translocon?

A

translation resumes and the growing protein is threaded through the translocon which continues to survey the growing protein looking for stretches of hydrophobic residues to form membrane-spanning domains- these residues retained in translocon until all TMDs are fully assembled then pass into ER membrane

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26
Q

what happens as the growing peptide emerges through the translocon into the ER lumen?

A

it is scrutinised by enzymes, protease cleaves any N-terminal signal sequence, N-linked glycosylation occurs, chaperone proteins (e.g. BiP) pull the growing peptide into the ER lumen, help it fold, other enzymes make additional modifications

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27
Q

what enzyme catalyses N-linked glycosylation, where and to which residues?

A

oligosaccharyl transferase, in ER lumen, to Asn residues within the sequence Asn-X-Ser/Thr

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28
Q

what is ERAD?

A

ER-associated degradation

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29
Q

why is ERAD necessary?

A

some proteins are damaged in the ER lumen, must be removed or they could aggregate and clog the system

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30
Q

what does ERAD do?

A

allows misfolded proteins to be returned to cytosol via pore associated with a ubiquitin ligase that attaches Ub to Lys residues on the protein marking it for degradation

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31
Q

what is defective in Parkinson’ disease?

A

Parkin which encodes subunit of ubiquitin ligase, prevents ERAD

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32
Q

how many ER proteins are marked for degradation?

A

more than 30%- system plays safe

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33
Q

what happens in the most common cause of cystic fibrosis?

A

CFTR protein is degraded by ERAD before it can reach plasma membrane to mediate Cl- transport

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34
Q

how does CMV hijack the ERAD pathway?

A

expresses protein that associates with the major histocompatibility complex (MHC) that would normally display proteins on cell surface to indicate cell is infected so virus can hide within the cell

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35
Q

is targeting proteins to the ER from the cytosol reversible?

A

no

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36
Q

what happens to the folded glycosylated proteins produced in the ER?

A

collected into COPII vesicles, conveyed to the cis Golgi

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37
Q

what happens to glycosylated proteins within the cis-Golgi?

A

sugar structures are trimmed and modified, proteins destined for lysosomes have sugars modified to include mannose-6-phosphate.

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38
Q

what do vesicles travel via?

A

microtubules

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39
Q

what are Rab proteins?

A

small G-proteins which act as identity labels for organelle membranes

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40
Q

what happens in the Rab cycle?

A

Rab-GDP recruited to an intracellular membrane, activated if host has specific proteins needed to make it shed GDP and attach GTP. if another organelle recognises the Rab-GTP and has the proteins needed to hydrolyse the GTP, does this, releasing the Rab, interacting with the original membrane

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41
Q

what do COPII coat proteins do?

A

bind to specific cytosolic sequence of proteins embedded in ER membrane, collect them into clusters which are pinched off as small COPII vesicles,
that move along microtubules to the cis-Golgi and shed coat on the way to unmask underlying identity labels

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42
Q

what proteins mediate fusion of COPII vesicles with the cis-Golgi?

A

SNARE (SNAP receptor) proteins

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43
Q

how do SNARE proteins work?

A

draw the 2 organelle membranes close together to mediate their fusion

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44
Q

what carries cargo back from the Golgi to the ER?

A

COPI vesicles

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45
Q

what recognises luminal cargo?

A

KDEL sequence that binds to membrane protein KEL receptor which assembles a COPI coat. vesicles pinched off, recognition and fusion at ER lumen

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46
Q

function of the trans Golgi?

A

sorts proteins to different destinations

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47
Q

how are soluble proteins destined for lysosomes recognised by the trans-Golgi?

A

by their M-6-P modification acquired in the Golgi

48
Q

what are M6P receptors?

A

membrane proteins that recognise M6P at their luminal surface, have short sequences that assemble a clathrin coat at their cytosolic surface

49
Q

what recognise the proteins bound to M6P receptors?

A

late endosomes which cause cargo to dissociate from the M6P receptors, pass them on to lysosomes

50
Q

what happens to the M6P receptors after endosomes remove their cargo?

A

they are sorted into vesicles and returned to trans Golgi

51
Q

what underlie an array of lysosomal storage diseases?

A

genetic deficiencies in the enzymes that are uniquely expressed in lysosomes

52
Q

treatment option for Gaucher disease (a lysosomal storage disease)?

A

administering M6P modified form of enzyme that is missing in the disease, which can be endocytosed by the M6P receptor and delivered to lysosomes

53
Q

purpose of endocytosis?

A

allows import of materials from outside cell and of endogenous materials from PM

54
Q

how is cholesterol imported from the plasma?

A

all cells express low-density lipoprotein receptors, bind to ApoB-100 component of LDL. cytosolic domain of LDL receptor has sequence that interact with AP2 and thereby clathrin, assembles LDL receptors with their LDL cargo into clathrin coated pits for trafficking to endosomes- in acidic lumen of endosome LDL dissociates from receptor + is recycled to PM, passes to lysosomes where ApoB-100 is degraded, freeing cholesterol to pass out of lysosome

55
Q

what is the fastest method of communication across the plasma membrane?

A

ion channels

56
Q

why is Ca2+ the ion used to regulate cellular activity?

A

the channels affect membrane potential, MP changes must be transduced into a messenger that enters the cell- this messenger is Ca2+ which can regulate many things such as release of neurotransmitter

57
Q

how do nicotinic ACh receptors in muscle work?

A

when 2 ACh molecules bind to the 2 alpha subunits, conformational change opens ion channel in protein which is equally permeable to Na and K

58
Q

structure of nAChRs?

A

pentameric with 2 alpha subunits, 1 beta, 1 delta, 1 gamma

59
Q

abilities required of ion channels?

A

must be able to open, close and select between ions

60
Q

common plan of voltage gated cation channels?

A

24 membrane spanning (4x6) regions arranged around central pore

61
Q

which voltage gated cation channels are formed from 1 protein chain, which is formed from 4 protein subunits?

A

Na+ and Ca2+ both formed from 1 chain, K+ formed from 4 proteins with 6 domains each

62
Q

what provides selectivity in voltage gated cation channels?

A

narrow ‘selectivity filter’ through which cations must pass in single file. allows surrounding amino acid residues to interact with permeating cation

63
Q

structure of selectivity filter of Ca2+ channels?

A

2 Ca2+ binding sites, each can bind Ca2+ selectively and tightly, when both occupies electrostatic repulsion between the 2 divalent cations causes 1 to be dislodged

64
Q

what closes ion channels?

A

channel residues at cytosolic tip of pore-linking helix (TMD6) come together like top of a teepee, occlude the channel

65
Q

what is the voltage sensor in VG ion channels? how does this lead to channels opening?

A

4 positively charged residues in TMD4 of each of 4 channel domains moves outwards in plane of membrane when PM depolarises, pulls on short cytosolic helix (links TMD4-5) causes twisting of pore-lining helices and splaying of teepee so ions can pass

66
Q

general features of signalling pathways initiated by allosteric receptor proteins?

A

receptor protein is what transmits information through its structure across PM, information passes onward through sequence of protein-protein and protein-small molecule interactions. many steps in pathway = amplification, allows cells to be very sensitive to extracellular stimuli. all steps in sequence are reversible. scaffold proteins arrange proteins into spatially-organised macromolecular complexes that allow effecive + specific information transfer. signalling pathways integrate information from other pathways

67
Q

how do receptor tyrosine kinases work?

A

extracellular signal binds, causes receptor to dimerise, dimerisation activates cytosolic tyrosine kinase activity on receptor, allows each subunit to transphosphorylate Tyr residues on the other. phospho-Tyr residues serve as docking sites for proteins with domains that binds phosphotyrosine

68
Q

what are proteins with domains that bind phosphotyrosine?

A

SH2 and PTB

69
Q

what sort of receptor is the insulin receptor?

A

a receptor tyrosine kinase

70
Q

how does the insulin receptor work?

A

starts out as a dimer. insulin binding rearranges dimer so that the intracellular tyrosine kinase is activated to cause transphosphorylation of the intracellular domains

71
Q

once the insulin receptor is activated what happens?

A

IRS-1 is recruited to phosphotyrosine by its PTB domain, IRS-1 protein then further phosphorylated to provide docking sites for other proteins. PI3K then phosphorylates PIP2 at the 3-position to give PIP3 which becomes scaffold around which other proteins are recruited. PIP3 recruits 2 proteins to PM: Akt2 and PDK1.

72
Q

how are Akt2 and PDK1 recruited to the plasma membrane?

A

their ‘bolt on’ PH domains which bind selectively to PIP3 and phosphorylate Ser and Thr residues

73
Q

what do Akt2 and PDK1 do?

A

they are protein kinases that phosphorylate Ser and Thr residues. once PDK1 recruited to PM it is activated, phosphorylates Akt2

74
Q

what happens after PDK1 phosphorylates Akt2?

A

Akt2 is further phosphorylated by mTORC2 to activate its kinase activity. Akt2 then phosphorylates substances to stimulate glycogen synthesis, and inhibit transcription of genes encoding proteins that synthesis glucose, and insert GluT4 r into PM to facilitate glucose uptake

75
Q

when is mTORC2 activated and when is Akt2 activity maximal?

A

mTORC2 is only active in fed state, maximal Akt2 activity occurs in fed cells stimulated with insulin

76
Q

what are the 2 major classes of allosteric receptors?

A

receptor tyrosine kinases and GPCRs

77
Q

how do GPCRs work?

A

when activated catalyse activation of G-proteins by causing them to release the GDP they have bound in inactive state and replace it with GTP- active (GTP-bound) G protein then signals onwards

78
Q

how does glucagon work?

A

glucagon receptor is a GPCR, stimulates formation of cAMP

79
Q

what is the ‘co-receptor’ expressed on T lymphocytes that is used to recognise coat proteins?

A

combined chemokine receptor (GPCR) and CD4 receptor

80
Q

how does Maraviroc work?

A

binds to recognition site of CCR5 chemokine receptor preventing it from binding HIV coat proteins so preventing HIV from infecting T cells

81
Q

how does vasopressin control water reabsorption in the kidney?

A

binds to the V2 receptor (GPCR), stimulates formation of cAMP-> insertion of aquaporins into PM of collecting tubules

82
Q

what causes congenital nephrogenic diabetes insipidus?

A

loss of function mutations in V2 receptor/mutations in aquaporins

83
Q

how does TSH stimulate release of hormones from thyroid glands?

A

binds to GPCR in thyroid cell membrane

84
Q

how do active GPCRs behave as exchange catalysts?

A

speed up the very slow dissociation of GDP from the inactive G protein by reducing activation energy of the reaction, so GTP can occupy the vacant guanine nucleotide-binding site

85
Q

what condition shows the importance of slow GDP dissociation?

A

in boys where the subunit of Gs protein αs is mutated so GDP now only binds weakly, spontaneous activating means protein is unstable at body temperature and stable in cooler testes, leading to male precocious puberty

86
Q

why is GDP dissociation slow?

A

if it wasn’t slow there would be no rate-limiting factor as a point of control for GPCRs

87
Q

how do GPCRs provide amplification?

A

single GPCR in its lifetime can activate many G proteins

88
Q

what terminates G protein activity?

A

intrinsic GTPase activity of G protein hydrolyses GTP to GDP

89
Q

what can accelerate intrinsic GTPase activity of G proteins?

A

RGS (regulators of G protein signals) proteins

90
Q

role of GPCRs in alcohol addicts (mouse models)?

A

stimulation of dopamine and GABAb receptors (GPCRs) signal through G protein Gi which inhibits cAMP formation. protein RGS6 enhances GTPase activity of Gi so deactivated more quickly, upregulated in alcoholic mice so more intense stimulation needed for same effect on cell. without RGS6 mice don’t become alcoholic

91
Q

shared features of RTKs and GPCRs?

A

extracellular surface recognises the signal, transmits info to PM to activate intracellular activity, both recruit intracellular proteins that are shared with other receptors so each GPCR doesn’t require own cohort of G proteins. signal cascades are amplifying.

92
Q

what are the subunits of G proteins activated by GPCRs?

A

3 subunits: βγ subunits are inseparable and anchored to PM. α subunits bind and hydrolyse GDP- there are 4 major families

93
Q

effect of choler toxin on αs?

A

covalent modification to block GTPase activity. cholera bacteria restricted to gut so primary symptoms result from over production of cAMP within gut epithelia

94
Q

effect of pertussis toxin on αi?

A

covalently modifies αi uncoupling it from GPCRs, - prevents activation

95
Q

what feature of a G protein determines whether it is GTP bound (active) or GDP bound (inactive)?

A

presence of a single γ-phosphate on bound guanine molecule- if present then 2 conserved residues in 2 distinct domains of the α-subunit make contact with it, pull switch regions in to activate G protein and break its contact with βγ subunit. then binding of GTP to α-subunit causes the G protein to dissociate from the GPCR. once α-GTP hydrolyses the GTP the subunits reassociate

96
Q

how does ACh interact with GPCRs in heart?

A

ACh released by parasympathetic nervous system, stimulates muscarinic GPCRs in heart that provoke coordinated response mediated by dissociated subunits of Gi that slow heart rate and reduce contraction force

97
Q

GPCR general structure?

A

extracellular N-terminal separated by 7 TMDs from cytosolic terminal. when activated cleft opens between cytosolic ends of TMD 3, 5, 6 and 7 for the α-subunit of the G protein to insert into

98
Q

how is cAMP made?

A

from ATP by adenyl cyclases

99
Q

how is cAMP inactivated?

A

by phosphodiesterases

100
Q

most important target of cAMP?

A

cAMP-dependent protein kinase (PKA)

101
Q

what G protein α subunit stimulates adenyl cyclases?

A

αs

102
Q

inhibitors of phosphodiesterases (which inhibit cAMP)?

A

caffein, theophylline, ventolin

103
Q

what stimulates PDE3, where does this occur?

A

PKA (stimulated by cAMP)- in vascular smooth muscle and platelets

104
Q

structure of protein kinase A?

A

tetramer of 2 regulatory (R) subunits (each binds 2 cAMP molecules) and 2 catalytic (C) subunits (phosphorylate substrates)

105
Q

how does PKA work?

A

2 R (regulatory subunits), block the active sites of the 2 C (catalytic) subunits, when R binds to cAMP occluded C active site is unblocked allowing the real protein substrates to be phosphorylated on Ser and Thr residues

106
Q

what are AKAPs?

A

scaffold proteins which associate with the R subunit of PKA to anchor PKA to different places in the cell and assemble related proteins (targets) within the PKA

107
Q

similarities of cGMP to cAMP?

A

made by guanylyl cyclases, degraded by PDEs, many actions mediated by PKG

108
Q

what is the target of Viagra?

A

PDE5, which degrades cGMP. prevents degradation of cGMP in blood vessels of penis causing them to dilate and blood to accumulate

109
Q

PLC (phospholipase C) signaling pathway?

A

substrate is PIP2 (lipid from which PIP3 is made. produces 3 intracellular messengers: DAG, IP3, decrease in concentration of PIP2 is also signal.

110
Q

what does DAG do after its is produced by PLC breaking down PIP2?

A

stays within PM, activates PKC

111
Q

what are phorbol esters?

A

molecules which look like DAG so are tumour promoting as they activate PKC but can’t be degraded

112
Q

what does IP3 do after it is produced by PLC breaking down PIP2?

A

water soluble so enters cytosol, stimulates Ca2+ release from the ER, Ca2+ used to regulate intracellular activities mostly through calmodulin

113
Q

how is DAG inactivated?

A

phosphorylation

114
Q

how is IP3 inactivated?

A

dephosphorylation

115
Q

how is PIP2 resynthesised?

A

products of deactivation of DAG and IP3 are re-united to resynthesise PIP2

116
Q

effect of Li+ on IP3 degradation?

A

blocks the final step (IP1 to inositol), this prevents PIP2 reformation

MIMS (15 decks)

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