Regulation of translation

Question 1

Is regulation of translation generally activation or repression?

Answer 1

Repression

Question 2

Which phases of general translation does regulation target?

Answer 2

It targets the initiation or elongation phase of translation

Question 3

What is the difference between general and specific translation?

Answer 3

General translation is what many/most mRNAs go through. This can be altered by global regulation effects such as cell stress, osmotic stress etc. Hence, many/most mRNAs are regulated by stress conditions.

Specific translation involves the regulation of translation of individual mRNAs, not at a global level. This kind of translation is very important for development

Question 4

What are the 2 critical steps in cap-dependent translation initiation? At which steps can translation be regulated?

Answer 4

1. Formation of ternary complex, containing EIF2 and GTP, initiating met-tRNA -> Goes to ribosome.
2. Formation of closed loop conformation, mediated on one hand by the cap-binding complex.

Both the ternary complex formation inhibition and mRNA activation can be inhibited/interfered with

Question 5

How can the formation of the ternary complex be inhibited?

Answer 5

During initiation and GTP hydrolysis, factors associated with GTP is no longer active. GDP can be recycled into new GTP with the help of eIF2B (also called guanine nucleotide exchange factor GEF) and eIF2. In other words, the normal (non-regulated) function of eIF2 is being a substrate for eIF2B for GTP to be recycled.

However, there are a couple of subunits among which some can be phosphorylated, such as the alpha-subunit of eIF2. These phosphorylation events have major regulatory potential. When eIF2alpha is phosphorylated by eIF2alpha kinases, eIF2 becomes a competitive inhibitor for GTP. The eIF2B is thus inhibited and enters an inactive state. In the inactive complex, the initiation factors eIF2 and eIF2B can no longer participate in the availability of ternary complex fold. This is an example of global repression of translation.

There are many kinases which can mediate this, the most important ones being HRI and PERK. There are various stress conditions which can lead to such a global block in translation.

Question 6

eIF2B / GEF (name meaning + function)

Answer 6

Guanine nucleotide exchange factor. Convert GDP back into GTP to keep the ternary complex active.

Question 7

What does phosphorylation of eIF2alpha do?

Answer 7

Converts eIF2 from a substrate for eIF2B, to a competitive inhibitor. Translated gets inhibited.

Question 8

What are the 2 most important eIF2alpha kinases?

Answer 8

HRI and PERK

Question 9

HRI

Answer 9

Heme-regulated inhibitor. Activated by heme depletion

Question 10

PKR

Answer 10

Protein kinase R. Activated by viral infection

Question 11

PERK

Answer 11

PRK-like endoplasmic reticulum kinase. Activated by endoplasmic reticulum stress.

Question 12

GCN2

Answer 12

General control non-depressible 2. Activated by amino acid starvation