Lecture 32 - alternative view by Rodwan Halimi XD

Question 1

What are the proteins that are produced in response to UPR?

Answer 1

GRP78 (BiP) and GRP94 are induced by the UPR.

Question 2

What are BIP levels like in normal cells and what is the difference compared to when there are misfolded proteins?

Answer 2

In normal conditions BIP is expressed in high levels.

These levels markedly increase in response to protein misfolding in the ER

Question 3

Most chaperones are said to be in the cytosol. What about in the ER?

Answer 3

Lots of chaperones found in ER compartment and this is to ensure the right type of folding takes place.

Question 4

What is the function of BIP?

Answer 4

Translocating nascent polypeptides.

Facilitating de noovo protein folding and assembly

Targeting misfolded proteins to ERAD machinery (ERAD machinery degrade misfolded protein in the cytosol).

Maintaining ER homeostasis.

Protein translation is slowed down to decrease amount of proteins in need of folding.

Question 5

What are the ER stress sensor proteins?

Answer 5

ATF6 (increases protein folding capacity and decreases transcription)

PERK

        (Translational control of                mRNA decay)

IRE1

Question 6

What are the ER stress triggers for apoptosis?

Answer 6

Prolonged ER stress

Too much ER stress

Question 7

What are the stages of the UPR/ER stress response?

Answer 7

Sensor: direct sensing occurs by multiple sensor proteins: IRE1, PERK, and ATF6.

Transducers: Multiple cytoplasmic regulatory mechanisms.

Effector: Multiple gene regulatory factors are activated.

Question 8

What is IRE1alpha?

Answer 8

IRE1alpha is a multidomain, evolutionarily conserved member of the UPR.

In higher eukaryotes IRE1 is a combination of IRE1alpa and beta these IRE1 sensors work in conjunction with 2 other sensor proteins.

Yeast only are controlled by 1 stress sensor.

Question 9

What are the domains of IRE1?

Answer 9

an ER lumen domain (sensor domain) which is an MHC-1 like structure with narrow peptide binding groove which is the site for GRP78 (BiP) binding.

A cytoplasmic domain (A signalling domain) which has 2 separate enzyme functions;
A kinase domain which phosphorylates Ser/Thr)
An RNAse domain (an endonuclease)

a transmembrane domain that sits in the ER membrane.