13. ER-proteins and lipids Flashcards Preview

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1

unfolded protein response

-sometimes too many unfolded proteins are produced at once, and this triggers the unfolded protein response:
ER has sensors that monitor levels of unfolded proteins
sensors are kept inactive by a chaperone called BiP
if too many unfolded proteins arise, BiP releases sensors, helps fold proteins, and the now active sensors alert the cell to make more chaperones
-sensors can also inactivate an initiation factor to prevent more protein synthesis

2

Heat shock proteins are chaperones

HSP
under heat stress, proteins can unfold and then fold back inappropriately
heat shock proteins recognize unfolded polypeptides
heat shock chaperones use energy from ATP hydrolysis to unfold mis folded polypeptides and allow them another chance to refold correctly
heat shock is not the only shock to induce HSPs; cold and anoxia will also induce them

3

how do HSP recognize mis folded proteins?

they look for hydrophobic regions on their surface. normal soluble proteins do not have such regions and the presence of such domains can lead to non specific protein-protein aggregation

4

exposure to a sublethal hight temperature can later_______the organisms from a later lethal _______ ________.

protect, heat shock
ex. bacteria exposed to 42 degrees c allows the cells to accumulate enough HSPs to protect them from a lethal 46 degrees c. same fore eukaryotes

5

elevated Hsp 70 expression protects against cardiac failure

hearts of transgenic mice that express elevate Hsp70 sustain less damage as a result of an experimental ischemic event

6

some diseases arise from protein mis-folding

kuru
scrapie
mad cow disease
variant creutzfeld-jacob disease (vCJD) in humans

7

kuru

neurological disorder first seen in fore people of new guinea
the people practiced cannibalism and ate their dead
once they stopped the appearance of the disease stopped

8

scrapie

a disease in sheep and goats, staggering gait, and strange behaviour such as scraping off the coat; due to neurological damage

9

mad cow disease

neurological damage causes loss of motor control
bovine spongiform encephalopathy-BSE
transmitted to humans

10

variant Creutzfeld-jacob disease (vCJD) in humans

brain develops holes, results in loss of neurological function

11

prion diseases:
prions and protein folding

the cause of kuru, scrapie, mad cow disease and vCJD is the presnece of abnormal forms of proteins, known as prions

12

prions act as "anti-chaperones"

changing shape of proteins into the wrong configuration

13

c
brain cells have a normal version of the prion protien -PrP

-it is made up mostly of alpha helices
-its found in a variety of tissues, but enriched in neurons
-its function is still not fully known
-the mutant/disease form of the protein is called PrP^Sc=it has the same amino acid sequence, and yet has mostly beta sheets

14

PrP^Sc

mostly beta sheet
acts as an anti chaperone, catalyzing the transformation of PrP^c into PrP^Sc
this process occurs within the cells of the central nervous system, and leads to severe neurological defects
there is no natural defence, since the protein responsible is so similar to one of our normal proteins

15

the change of normal PrP^c into mutant PrP^Sc takes a ________time to accumulate

long

16

why don't the improperly folded proteins get removed?

their shape may somehow protect them from being processes by the cell's machinerywe12we that removes mis folded proteins

17

what happens if chaperones can't correct the misfolded proteins ?

mis folding of proteins can easily happen when they are first made, and if chaperones can't correct the misfolded proteins, they are bound to BiP, a chaperone, which transports them into the cytoplasm by reverse translocation through a translocon. they are bound by ubiquitin and destroyed by proteasomes

18

proteasome

protein-degrading machine
-protein structure, not a membrane-bound compartment
-located w/in the cytoplasm and w/in the nucleoplasm
-both prokaryotes and eukaryotes have them
-direct uptake of proteins from cytoplasm/nucleoplasm
three related functions

19

Three proteasome functions

housekeeping
removal of improperly folded proteins
removal of ubiquitin-tagged proteins

20

proteasome housekeeping

-clearance of cytoplasm and nucleoplasm proteins
-each type of protein has a set half-life in the cytoplasm (steady turnover)
*metabolic enzymes, hemoglobin, structural proteins tend to last longer:days to weeks
*regulatory molecules such as those that regulate DNA replication, are required only at certain times (S-phase) and have a short life. their presence can be controlled by synthesis
*N-end rule: protein half-life correlates to the (single) N-terminal amino acid.
- if N-terminal is Arginine, Lysine: the protein lasts 2-3 min in cytoplasm
-if it is Cal, Met, protein lasts >30 hrs

21

half life

the time it takes for 50% of the protein present at time = 0 to be destroyed

22

proteasome removal of improperly folded proteins

mis folded proteins are ejected from the RER back to cytoplasm by the translocon pores, then degraded by the proteasomes

23

proteasomes removal of ubiquitin-tagged proteins

-a regulated step
-allows cell to remove certain proteins as needed(eg. cyclin)
-ubiquitin is a small, highly conserved protein
-ubiquitin ligase, a family of related proteins recognize proteins destined for destruction, adds ubiquitin units
-single ubiquitin on cytoplasmic face of trans-membrane proteins directs proteins to endosomes
-multiple ubiquitin chains direct cytosol proteins to proteasomes

24

Proteasome structure

a barrel like unit made of globular proteins
four rings, seven subunits each
cap protein
beta subunits (proteolytic function
alpha subunits
together, these create a 13 angstrom opening
proteins must be unfolded and threaded into the interior

25

proteasome in action

1.protein tagged by a chain of ubiquitin molecules
2.protein-ubiquitin complex binds to the cap protein
3.ubiquitin removed and protein unfolded by the cap and then fed through the alpha-subunit gap
4.beta subunits degrade protein to short peptides, return to cytoplasm

26

membrane biosynthesis in the ER

a) membrane orientation
b)membrane synthesis
c)membrane modification

27

membrane orientation

-remember inner/outer orientation is maintained as membranes bud/fuse or interconnect- mitochondrial and chloroplast membranes are not directly connected to most others
-inner and outer surfaces of the membranes have diff lipid compositions (compositional asymmetry)
-cells membranes of diff organelles have diff lipid compositions
-NOTE: orientation of proteins and lipids are retained as vesicles move

28

lipid bilayer is the basic structure of cell membranes. based on:

fat soluble tails in the interior
water soluble polar portions on their surfaces (either side of membrane)

29

membrane synthesis

the lipid component of cell membranes is made primarily in the SER and then transferred to other locations. membranes are made by inserting new lipids into existing membrane

30

6 facts on membrane synthesis

1. membranes are made primarily of the major phophoglycerides
-phosphatidyl serine (PS)
-phosphatidyl choline (PC)
-phosphatidyl ethanolmine (PE)
2.other specialized lipids are started in ER but will be completed in the Golgi. E.g sphingomyelin and glycolipids
3. mitochondrial and chloroplast membranes are partial exceptions-some components of those membranes are made locally
4.membrane lipids are made by integral membrane proteins of the ER
5.new lipid molecules are inserted on the cytosolic side of the membrane (towards cytoplasm, not the lumen)
6. half of the new lipid molecules are turned to the lumen side of the membrane by other enzymes called flippases