#11589 inhibition of APC-Cdc20 complex activity

[Valerie Wood]

GO:0060565
inhibition of APC-Cdc20 complex activity
Biological ProcessDefinitionAny process that prevents the activation of APC-Cdc20 complex activity regulating the mitotic cell cycle.

There are a number of problems with this term, and its annotations.

1. Biology
   As far as I am aware the only think which inhibits the APC-cdc20 complex is the MCC (mitotic checkpoint complex). It does this by blocking its substrate binding sites and repositioning Cdc20 away from the APC/C subunit Apc10 22898774, Fig 1
   https://sourceforge.net/p/geneontology/ontology-requests/11573/

2. Existing term issues
   The existing term has lots of annotations to F-box proteins which are nothing to do with the inhibition of the complex (they are substrate adaptors). Some of the annotations appear to be related to SCF ligase, not APC. I suggest we obsolete this term and start again…

The existing term is not defined fully it should be “Any process that prevents the activation of APC-Cdc20 complex activity regulating the mitotic cell cycle metaphase /anaphase transition”.

1. Suggested fix:
   I think we need a replacement Molecular Function term to describe the activity of the MCC against the APC-Cdc20 complex

A molecular function which prevents the activation of the APC-Cdc20 complex activity to negatively regulate the mitotic metaphase anaphase transition.
It would have a F-P link to negative regulation of the metaphase/anaphase transition.
The only gene products which would be annotated to this term would be MCC members (excluding Cdc20 itself).

If we don’t want to do this (there is a precedent for the APC which I have followed previously but I am not sure we would want to do this on a complex by complex basis). If not we would need something like:

“ubiquitin ligase inhibitor activity” and could use extensions to say which complex, and we wouldn’t be able to add any F-P links we would need to do this at annotation time.

[Valerie Wood]

Actually, I see a suitable parent exists for the replacement term:

GO:0061637 mitotic anaphase-promoting complex inhibitor activity
Decreases the activity of a mitotic anaphase promoting complex, an ubiquitin-protein transferase activity that regulates the mitotic metaphase/anaphase transition.

This should be redefined as
prevents the activation a mitotic anaphase promoting complex, a ubiquitin-protein transferase activity that regulates mitotic cell cycle transitions.

The existing regulates relationship to
GO:0090302 APC-Cdc20 complex activity
should be deleted (there are two forms of the APC and one of them regulates the metaphase/anaphase transition (above), the other one regulates mitotic exit
so this relationship is not always true.

This relationship should be added back for the new descendent term, described above.

[Valerie Wood]

Finally I need a new term to describe the process of negatively regulating the other APC,

negative regulation of the APC-fizzy related complex activity
as a child of
GO:1903834 regulation of APC-fizzy related complex activity
(note to self change existing Cdc2 annotation to this term from "inhibition of APC-Cdc20 complex activity")

[Valerie Wood]

figure to demonstrate the MF of the MCC

[Tanya Berardini]

Added this term through TG:

[Term]
id: GO:1904190
name: negative regulation of APC-fizzy related complex activity
namespace: biological_process
def: "Any process that stops, prevents or reduces the frequency, rate or extent of APC-fizzy related complex activity." [GO_REF:0000059, GOC:TermGenie, GOC:vw]
synonym: "down regulation of APC-fizzy related complex activity" EXACT [GOC:TermGenie]
synonym: "down-regulation of APC-fizzy related complex activity" EXACT [GOC:TermGenie]
synonym: "downregulation of APC-fizzy related complex activity" EXACT [GOC:TermGenie]
synonym: "inhibition of APC-fizzy related complex activity" NARROW [GOC:TermGenie]
is_a: GO:0051444 {is_inferred="true"} ! negative regulation of ubiquitin-protein transferase activity
is_a: GO:1903834 {is_inferred="true"} ! regulation of APC-fizzy related complex activity
intersection_of: GO:0065007 ! biological regulation
intersection_of: negatively_regulates GO:0090622 ! APC-fizzy related complex activity
relationship: negatively_regulates GO:0090622 {is_inferred="true"} ! APC-fizzy related complex activity
created_by: tb
creation_date: 2015-05-05T21:45:35Z

[Tanya Berardini]

The plan:

(1) New term:

APC-Cdc20 complex inhibitor activity
is_a GO:0061637 mitotic anaphase-promoting complex inhibitor activity
part_of negative regulation of the metaphase/anaphase transition.

Def: prevents the activation of the APC-Cdc20 complex activity to negatively regulate the mitotic metaphase anaphase transition.

(2) delete relationship of GO:0090302 APC-Cdc20 complex activity to GO:0061637

(3) redefine GO:0061637

prevents the activation a mitotic anaphase promoting complex, a ubiquitin-protein transferase activity that regulates mitotic cell cycle transitions.

Does that seem right? If yes, I'll do this tomorrow.

[Valerie Wood]

Yep,

Although I don't see
2) delete relationship of GO:0090302 APC-Cdc20 complex activity to GO:0061637

but possibly that got done already?

Val

[Tanya Berardini]

Yes, looks like (2) was done. I was going off the SF issue only, without checking the ontology. Whoops.

[Tanya Berardini]

I'll send an obsoletion email out tomorrow. Do you think the new MF term should be a replace or a consider alternative for the BP term to be obsoleted?

[Valerie Wood]

consider.....with care. Many of the existing annotations to the term have nothing to do with "inhibition of APC-Cdc20"
Maybe an accompanying comment.

this term is only for gene products which bind to and directly inhibit the APC-Cdc20 complex (i.e the MCC complex)
APC-Cdc20 complex inhibitor activity

As far as i'm aware MCC is the only APC inhibitor.

[Tanya Berardini]

Sent today:

Dear all,

The proposal has been made to obsolete:

GO:0060565, inhibition of APC-Cdc20 complex activity

Reasons for obsoletion and a proposed alternative term are discussed in the following Sourceforge issue:

https://sourceforge.net/p/geneontology/ontology-requests/11589/

Please review the above issue for full details and to make comments.

There are 17 total annotations to this term from UniProtKB, CGD, MGI, RGD, PomBase, and ZFIN.

http://amigo.geneontology.org/amigo/term/GO:0060565

Unless objections are received by May 21st, we will assume that you agree to this change. Please direct all comments to the SF issue mentioned above.

Thanks,

Tanya Berardini
on behalf of the Ontology Editors group

[Tanya Berardini]

Term obsoleted with consider term, definitions modified, new term created.

id: GO:0060565
name: inhibition of APC-Cdc20 complex activity
namespace: biological_process
-def: "Any process that prevents the activation of APC-Cdc20 complex activity regulating the mitotic cell cycle." [GOC:dph, GOC:tb]
+def: "OBSOLETE. Any process that prevents the activation of APC-Cdc20 complex activity regulating the mitotic cell cycle." [GOC:dph, GOC:tb]
+comment: This term was made obsolete because it was not clearly defined and thus used incorrectly in annotation.
synonym: "inhibition of APC activity during mitotic cell cycle" EXACT [GOC:dph, GOC:tb]
synonym: "inhibition of APC/C activity during mitotic cell cycle" RELATED [GOC:dph, GOC:tb]
synonym: "inhibition of cyclosome activity during mitotic cell cycle" RELATED [GOC:dph, GOC:tb]
synonym: "inhibition of mitotic anaphase-promoting complex activity" RELATED [GOC:vw]
-is_a: GO:0060564 ! negative regulation of APC-Cdc20 complex activity
+is_obsolete: true
+consider: GO:0090645

[Term]
+id: GO:0090645
+name: APC-Cdc20 complex inhibitor activity
+namespace: molecular_function
+def: "Prevents the activation of the APC-Cdc20 complex activity to negatively regulate the mitotic metaphase anaphase transition." [GOC:vw]
+comment: this term is only for gene products which bind to and directly inhibit the APC-Cdc20 complex (i.e the MCC complex).
+is_a: GO:0061637 ! mitotic anaphase-promoting complex inhibitor activity
+relationship: part_of GO:0045841 ! negative regulation of mitotic metaphase/anaphase transition
+created_by: tanyaberardini
+creation_date: 2015-05-21T14:44:43Z

[David Osumi-Sutherland]

Looking at the parent class:

label: 'APC-Cdc20 complex activity'
definition: "A ubiquitin-protein ligase activity that increases the rate or extent of the metaphase to anaphase transition of the mitotic cell cycle."
has_exact_synonym: "ubiquitin-protein ligase activity involved in positive regulation of mitotic metaphase/anaphase transition"
EquivalentTo: 'ubiquitin protein ligase activity'
and ('part of' some 'positive regulation of mitotic metaphase/anaphase transition')

I'm not comfortable with the name here, as it at least sounds like an activity defined for a complex. It is especially problematic in combination with the definition and the logical definition, as it is entirely possible that other complexes will be found to have this activity in this process context.

I think that the name should be changed to the exact synonym shown above, with the label becoming a narrow synonym. If the name stays (which I don't think would be a good idea), the Equivalent Class expression has to go and the definition should mention APC-Cdc20 in some way.

There is a similar issue with this term, but without the complication of an equivalent class axiom:

label: "APC-fizzy related complex activity"
definition: "A ubiquitin-protein ligase activity that increases the rate or extent of the mitotic exit."

We shouldn't assume that no other complex will ever be found that has "ubiquitin-protein ligase activity that increases the rate or extent of the mitotic exit."

[David Osumi-Sutherland]

General note:

"As far as I am aware, the only thing that inhibits the APC-cdc20 complex is the MCC (mitotic checkpoint complex)."

Shouldn't be relevant given our commitment to following the Open World Assumption in GO.

comment: this term is only for gene products which bind to and directly inhibit the APC-Cdc20 complex (i.e the MCC complex).
>
comment: this term is only for gene products which bind to and directly inhibit the APC-Cdc20 complex (e.g.the MCC complex).

[Valerie Wood]

OK leave (i.e the MCC complex) off the comment. It could change I guess but it would be a paradigm shift in biology.

It doesn't change the fact that the existing annotations are incorrect. The only thing which fits this def currently is the MCC. If something else appears it could be annotated to this term, but at present there isn't anything else known which fits this def.

The example was meant to help people to figure this out, but leave it off if it makes things difficult (I though it would be OK in a comment).

If you think the terms themselves are inappropriate, I'd also be happy to obsolete these too. They are functions of complexes. I am using them because they existed for some Ub ligases.....

V

[Valerie Wood]

A summary of the biology is that
MCC inhibits the APC-cdc20 (there are other varieties of APC)
APC is a ubiquitin ligase complex

I don’t know what is best perhaps just use “inhibition of ubiquitin ligase activity” and somehow specify the specific ubiquitin ligase in an extension?

I'd be happy to do this instead:

inhibition of ubiquitin ligase activity
with extensions
i) has_direct_input(APC-cdc20 complex ID),
and
ii) part_of negative regulation of metaphase /anaphase transition

[Valerie Wood]

I do think these terms are a big problem.
The term
GO:0090302 APC-Cdc20 complex activity
is defined
A ubiquitin-protein ligase activity that increases the rate or extent of the metaphase to anaphase transition of the mitotic cell cycle.

BUT, this is not the ONLY ubiquitin ligase which affects the mitotic metaphase anaphase transition. This is the final step, responsible for the degradation of securin. However, upstream it seems that the SCF ubiquitin ligase complex regulates the APC activator cdc20/slp1 and so is also involved in the m/a transition (and so fits this def).

SO the term name here is narrower in scoe than the definition.

I know that we (PomBase) have requested some of these specific "ligase complex activity" terms and their associated inhibitors/activators- this was because some terms were already established (to create F-P links within the ontology from specific ubiquitin ligases to their regulated processes, possibly for LEGO modelling) , and we followed a precedent

I strongly believe that this practice is too complicated and unsustainable.
It would be difficult to create a x ubiquitin ligases complex activity linking to the multiple processes which ubiquitin ligases regulate. Multiple processes are regulated, sometimes simultaneously, and sometimes at different time points. This makes it impossible to create F-P links. For example the APC-cdc20 has a role at mitosis and at meiosis. Therefore you would need to create either meiosis and mitosis specific variations of these activities linking to the specific processes regulated by each.
This makes annotation really complicated and the ontology graph is difficult to interpret.

My suggestion would be to strip these back to plain old
ubiquitin ligase activity
ubiqtitin ligase activator
ubiquitin ligase inhibitor

and we capture the links to specific substrates (Ie which Ub ligase or Ub ligase complex is activated of inhibited) and which process is regulated using annotation extensions. Its much more manageable to create these F-P links at annotation time than to hard code them in the ontology.

[Tanya Berardini]

Argh. It looks like my comment from last Friday didn't get save. Reconstructing..

Is the idea then to propose obsoletion of the following?

GO:0090302 APC-Cdc20 complex activity (and related terms with the 'APC-Cdc20 complex activity' string in the name)

GO:0090622, APC-fizzy related complex activity (and related terms with the 'APC-fizzy related complex activity' string in the name)

[Valerie Wood]

I think it isn't a bad idea to obsolete (or merge?) any 'activities' which refer to specific ligases, and add a comment to use extensions to capture this detail. Maybe something which needs discussion at the editors level to get more input? Its more of a suggestion to deal with a "these branches could get a bit crazy if we continue down this route" scenario.
v

[Tanya Berardini]

Will put onto GO editors meeting agenda.

[Tanya Berardini]

I was rereading this and the related issue again before putting it on the editors agenda for tomorrow and it's clear to me that we should backtrack and do what you suggest "obsolete any 'activities' which refer to specific ligases [or ligase complexes], and add a comment to use extensions to capture this detail."

Otherwise it gets too complicated and, as we've seen with Antonia's example with mes1, inferred annotations are incorrect.

[David Osumi-Sutherland]

+1

[Tanya Berardini]

I'm going to send an obsoletion email for these:

GO:0090302 APC-Cdc20 complex activity (and related terms with the 'APC-Cdc20 complex activity' string in the name)

GO:0090622, APC-fizzy related complex activity (and related terms with the 'APC-fizzy related complex activity' string in the name)

Are there any other terms that we should include in the notification?

[Valerie Wood]

Using the same logic, all of these would need to go back to the ubiquitin ligase MF term

GO:0051488 activation of anaphase-promoting complex activity
GO:0051487 activation of anaphase-promoting complex activity involved in meiotic cell cycle
GO:0061636 mitotic anaphase-promoting complex activator activity
GO:0061637 mitotic anaphase-promoting complex inhibitor activity
GO:0090645 APC-Cdc20 complex inhibitor activity
GO:0007092 activation of APC-Cdc20 complex activity
GO:0090623 activation of APC-fizzy related complex activity
GO:1903834 regulation of APC-fizzy related complex activity
GO:0060564 negative regulation of APC-Cdc20 complex activity
GO:1903835 positive regulation of APC-fizzy related complex activity
GO:1904190 negative regulation of APC-fizzy related complex activity
GO:0051488 activation of anaphase-promoting complex activity
GO:0051487 activation of anaphase-promoting complex activity involved in meiotic cell cycle

VAL