parent for GO:1990565 HSP90-CDC37 chaperone complex?

[gocentral]

On Paola's advise, I'm adding it here. To be discussed on Editors' call.

GO:1990565 HSP90-CDC37 chaperone complex currently hasn't got a logical parent apart from 'protein complex'. I would like to add something more specific but we only know the process rather than the function of the complex so we can't use our usual complex_by_activity inference.

[Term] id: GO:1990565 name: HSP90-CDC37 chaperone complex namespace: cellular_component def: "A protein complex involved in stress-induced mitophagy (mitochondrial degradation). In mammals it consists of heat shock protein HSP90 and its co-chaperone CDC37. Experimental evidence suggests that the complex enables the autophosphorylation of ULK1. Phosphorylated ULK1 in turn phosphorylates ATG13 which is an essential step in mitophagy. HSP90-CDC37 binding prevents rapid ubiquitin-dependent proteosomal degradation of its targets. " [GOC:bhm, IntAct:EBI-9990131, IntAct:EBI-9990540, PMID:21855797, PMID:22939624] comment: An example of this is HSP90AB1 in human (P08238) in PMID:21855797 (inferred from direct assay). subset: termgenie_unvetted is_a: GO:0043234 ! protein complex is_a: GO:0044444 {is_inferred="true"} ! cytoplasmic part relationship: capable_of GO:0019887 ! protein kinase regulator activity relationship: capable_of_part_of GO:0032435 ! negative regulation of proteasomal ubiquitin-dependent protein catabolic process relationship: capable_of_part_of GO:0045737 ! positive regulation of cyclin-dependent protein serine/threonine kinase activity relationship: capable_of_part_of GO:1903599 ! positive regulation of mitochondrion degradation relationship: part_of GO:0005737 ! cytoplasm

I would like to create a term that describes its pos reg action in the phosphorylation chain that leads to mitophagy initiation. 'regulatory complex' is too generic and 'protein kinase complex' slightly out of scope as the paper does not describe the actual kinase activity, just that the inhibition of HSP90 leads to a drastic reduction of phosphorylated downstream targets.

Please discuss!

Birgit

Reported by: bmeldal

Original Ticket: geneontology/ontology-requests/11356

[gocentral]

Update: I just read the following review: 19387550 and it is clear that the above def is way to narrow (it's just of many one cases!)

The def should be changed to: "A protein kinase chaperone complex required for the proper folding, maturation and stabilization of target proteins (mostly signalling protein kinases, some steroid hormone receptors), usually during or immediately after completion of translation. The highly conserved, phosphorylated CDC37-Ser13 (vertebrates) or cdc37-Ser14 (yeast) is essential for complex assembly and target protein binding. CDC37-Ser13 (Ser14) is phosphorylated by Casein kinase II (CK2), which in turn is a target of CDC37 creating a positive feedback loop. Complex binding also prevents rapid ubiquitin-dependent proteosomal degradation of target proteins."

And the parent could be 'chaperone complex". There are already a few chaperone complexes in the GO but they are just direct children of protein complex. There is no activity (GO:0003754 chaperone activity has been obsoleted) to infer the complex term from directly.

Sorry about the mess, shot without aim again...

Birgit

Original comment by: bmeldal

[gocentral]

Note for self: I need to review all of this and, if necessary, add to agenda for editors' call.

Original comment by: paolaroncaglia

[gocentral]

Hi Birgit,

Let’s focus on ‘chaperone complex’ first. Def and placement of ‘HSP90-CDC37 chaperone complex’ will follow accordingly.

If you look at the QuickGO entry for the obsolete term GO:0003754 chaperone activity, you can see suggestions for other terms you could use instead, including two MFs:

protein binding involved in protein folding (“Interacting selectively and non-covalently with any protein or protein complex (a complex of two or more proteins that may include other nonprotein molecules) that contributes to the process of protein folding.”) broad synonym: chaperone activity

and

unfolded protein binding (“Interacting selectively and non-covalently with an unfolded protein.”) related synonym: chaperone activity

(http://www.ebi.ac.uk/QuickGO/GTerm?id=GO:0003754)

Is the expression ‘chaperone complex’ commonly used in the literature? If yes, we could add it in GO and give it a logical def pointing to one of the MFs above. We’d have to be careful and limit it to the ‘binding’ bit, i.e. excluding transport. Your suggested revised def for HSP90-CDC37 chaperone complex doesn’t refer to transport, in fact. The chaperone issue was discussed in 2008-2009, so if you could please suggest a carefully phrased def for ‘chaperone complex’ and suggest logical defs, I’ll then run it by editors who might have memory of that discussion (note for self: include Val).

As for ‘HSP90-CDC37 chaperone complex’, your suggested new def “A protein kinase chaperone complex…”. So the generic complex contains a protein kinase and a chaperone (at least), and, I presume, is capable of protein kinase activity at all times. So, ‘HSP90-CDC37 chaperone complex’ could and should be is_a ‘protein kinase complex’ and that itself would take it out from under the broader ‘protein complex’ bin, if or until we can’t find an agreement on ‘chaperone complex’. Shall I do that?

Note for self: if ‘chaperone complex’ is created, existing CC terms containing ‘chaperone’ and ‘complex’ in their name should be made children of it.

Thanks, Paola

Original comment by: paolaroncaglia

[gocentral]

Hi Paola,

Happy New Year!

Chaperone complex def: A protein complex required for the non-covalent folding or unfolding, maturation, stabilization or assembly or disassembly of macromolecular structures. Usually active during or immediately after completion of translation. Many chaperone complexes contain heat shock proteins.

Comment: An example of this is HSP90AB1 in human (P08238) in PMID:21855797 (inferred from direct assay).

is_a: GO:0043234 ! protein complex relationship: capable_of GO:0044183 protein binding involved in protein folding

NB: I can't think or any other logical defs.

Wikipedia: http://en.wikipedia.org/wiki/Chaperone_%28protein%29

As for ‘HSP90-CDC37 chaperone complex’: It is not a kinase itself but it's targets are almost exclusively protein kinases. Maybe my phrasing was incorrect and should just read 'A chaperone complex required for the proper folding, maturation and stabilization of target proteins...'.

Note: the chaperonin complex would also be children, e.g. GO:0016465 chaperonin ATPase complex

I hope I addressed all points above - for now :)

Birgit

Original comment by: bmeldal

[mcourtot]

Hi @ValWood: @bmeldal proposes a NTR "chaperone complex" defined as

A protein complex required for the non-covalent folding or unfolding, maturation, stabilization or assembly or disassembly of macromolecular structures. Usually active during or immediately after completion of translation. Many chaperone complexes contain heat shock proteins.

Comment: An example of this is HSP90AB1 in human (P08238) in PMID:21855797 (inferred from direct assay).

is_a: GO:0043234 ! protein complex
relationship: capable_of GO:0044183 protein binding involved in protein folding

@paolaroncaglia mentioned you were part of the 2008-2009 chaperone discussions; would you be able to weigh in as to whether this term is ok or not in the light of those?

[ValWood]

Yes. This supports my request that GO:0044183 protein binding involved in protein folding be renamed to "protein folding chaperone activity" to be more understandable to biologists....

[mcourtot]

Looking at metallochaperone complex - should they infer under chaperone complex?

[mcourtot]

I created chaperone complex and changed the definition of HSP90-CDC37 chaperone complex/ I moved the existing chaperone/chaperonin under chaperone complex. Question remains for metallochaperone complexes, currently defined as 'macromolecular complex' and ('capable of' some 'metallochaperone activity'). If needed, please open a separate ticket.

[ValWood]

Actually I think there could be a problem. Chaperone isn't a single activity, its a collection of activities.

So the def: A protein complex required for the non-covalent folding or unfolding, maturation, stabilization or assembly or disassembly of macromolecular structures. Usually active during or immediately after completion of translation. Many chaperone complexes contain heat shock proteins.

Is a problem to logically define using GO:0044183 protein binding involved in protein folding

which refers specifically to a "protein folding chaperone"

I'm not completely sure what the solution is for chaperones. I always feel we need more precise terms for the activities of various flavours of chaperone (of which metallochaperone is one).

This one isn't going to be an easy one....

[mcourtot]

I think that when we say "chaperone complex capable of GO:0044183 protein binding involved in protein folding" we don't imply that it is the only thing it is capable of, so this is at least not wrong. We could add different activities if needed?

[ValWood]

OK go with it. The rest is for another day ;)

[mcourtot]

well I still would like it to be clean if possible ;) If we want to keep the general chaperone complex term we should make sure that, as you mention, other flavours of chaperone infer properly under it - at least for those we already have - thus the question for the metallochaperone. I'll create a new ticket to not confuse this one. Thanks for the feedback @ValWood !