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This repository hosts the tracker for issues pertaining to GO annotations.
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Matrix: tRNA metabolism /cytoskeleton #2540

Open ValWood opened 5 years ago

ValWood commented 5 years ago

FB:FBgn0031604 Elp3

elongator is no longer thought to be a histone acetyltransferase: Elp3 Elongator complex protein 3 histone acetylation FlyBase Drosophila melanogaster IMP protein FB:FBrf0227478 PMID:25578876 20150618

Lots of indirect phenotypes here: Elp3 Elongator complex protein 3 cytoskeletal matrix organization at active zone FlyBase Drosophila melanogaster IMP protein FB:FBrf0216903 PMID:22153374 20120614 Elp3 Elongator complex protein 3 peptidyl-lysine acetylation FlyBase Drosophila melanogaster IDA protein FB:FBrf0216903 PMID:22153374 20120614

ValWood commented 5 years ago

see https://github.com/geneontology/go-annotation/issues/1965 and tickets within for more background

ValWood commented 5 years ago

These also seem like old "Elongator" phenotypes

poly | poly |   | oocyte microtubule cytoskeleton polarization |   | FlyBase | Drosophila melanogaster | IDA |   |   | protein |   | FB:FBrf0211064PMID:20473032 | 20110317

  | poly | poly |   | melanotic encapsulation of foreign target |   | FlyBase | Drosophila melanogaster | IMP |   |   | protein |   | FB:FBrf0217123PMID:21947570 | 20120308

hattrill commented 5 years ago

Interesting......in Fig 7 PMID:22153374 (2011) they show that recombinant Elp3 can autoacetylate and acetylate histone H3 and branchpoint (an active zone cytoskel protein) but not tubulin.

ValWood commented 5 years ago

Yep it's know to acetylate histones in vitro. This seems to have been a red herring for a long time. It has a GNAt domain, so it probably does function as an acetylase or acetylase-like reaction in the tRNA wobble base 5-methoxycarbonylmethyl-2-thiouridinylation/elongator complex

ValWood commented 5 years ago

this aligns with the current view https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4615193/ see also https://github.com/geneontology/go-annotation/issues/1965 lots o recent papers and references

One paper does mention other substrates might be direct, but so far this seems unlikely

hattrill commented 5 years ago

They seem to like branchpoint as a target in vivo and in vitro....I think that I will have to contact the authors on this. This is the current gene snaphot, provided by an 'expert in the field' (I'll have to dig to find out who): "Elongator complex protein 3 (Elp3) encodes a Lysine (K) acetyltransferase (KAT) that resides primarily in the cytoplasm of neurons. It acetylates the product of brp in an opposite reaction to the product of HDAC6 to regulate T-bar morphology and function, and unlike most KATs it does not acetylate histones." [Date last reviewed: 2019-03-07]

hattrill commented 5 years ago

Sorry ...typo....I meant bruchpilot - a neuronal cytoskeletal protein

hattrill commented 5 years ago

In flies, we have a lot of papers supporting its role in neuronal activity - there seems to be some confusion in the past with regard to what it does to tubulin and histones - the current answer to that is 'not much'. I will dig around some more...

hattrill commented 5 years ago

So this is good for the tRNA function: The Elongator subunit Elp3 is a non-canonical tRNA acetyltransferase. PMID:30733442

ValWood commented 5 years ago

They used to think that it did loads of things in yeast, but overexpressing tRNA lysine fixed every phenotype! It's would be unusual for tRNA metabolism proteins to moonlight ....

Anyway I can make just a drosophila exception if you think it is convincing.

ValWood commented 5 years ago

The Elongator subunit Elp3 is a non-canonical tRNA acetyltransferase. PMID:30733442

Great, that is the first actual evidence for the MF in tRNA metabolism (from any species as far as I'm aware)

ValWood commented 5 years ago

Yipee!

Our results define Elongator and its Elp3 subunit as a genuine tRNA editing enzyme in all three domains of life and resolve the ongoing debate about a direct involvement of Elongator in any cellular activity other than tRNA modification.

The key role of Elongator in maintaining the stringent homeostasis of the cellular proteome explains the pleotropic phenotypes associated with Elp3 deficiency, including neurogenesis30, DNA repair31, exocytosis32, genome demethylation33, protein acetylation34,35, mitochondria dysfunction36, and tRNA modification22. Moreover, patient-derived mutations and deficiencies in different Elongator subunits are associated with severe human diseases37,38, such as cancer39 and neurodegenerative diseases40, including familial dysautonomia41, amyotrophic lateral sclerosis42, intellectual disabilities43, and ataxia44

I shall use this reference for all future elongator whack-a-mole!

hattrill commented 5 years ago

I am going to contact the guy who did the gene snapshot - as his summary says that it is not a HDAC, even if it does acetylate brp - I'd like to get some clarifcation as it is quite important in neuronal disease models.