issues with cap binding complexes

[ValWood]

current arrangement RNA cap binding complex --mRNA cap binding complex ----GO:0098745 Dcp1-Dcp2 complex ----GO:0034519 cytoplasmic RNA cap binding complex --nuclear cap binding complex

However there don't appear to be any cap binding complexes specific for mRNAs ..the nuclear cap binding complex members could also be annotated to the sibling term mRNA cap binding complex. In fact nuclear cap binding complex has narrow mRNA cap binding complex

• [x] obsolete "mRNA cap binding complex"
  • [x] GO:0098745 Dcp1-Dcp2 complex is_a GO:0034519
  • [x] nuclear cap binding complex is defined to use for a very specific complex (CBC), rename CBC cap binding complex (it isn't restricted to the nucleus, so the name is confusing)

[ValWood]

There are 2 versions of the "nuclear" cap complex NCBP1 and NCBP2 or NCBP1 and NCBP3 (a new variant, which also appears to be conserved)

[ValWood]

• [x] rename GO:0098745 Dcp1-Dcp2 complex "RNA decapping complex"
  (it would be better if the others could be named functionally too)

[pgaudet]

@bmeldal does that proposal seem OK to you ? @krchristie I thought you looked at similar terms recently; maybe you have input on this proposal ?

Thanks, Pascale

[krchristie]

@pgaudet - I have worked on cap structure terms, but not recently. My recollection is that I would tend to agree with @ValWood that the kind of cap on eukaryotic mRNAs is not specific to mRNA. However, I was also under the impression that there a couple different kinds of RNA caps in eukaryotes, so it might be worth checking if there is any need to distinguish between cap binding complexes that distinguish between the two kinds of caps.

Also, interestingly, it seems that NAD+ based caps have been found on some RNAs in E. coli: https://academic.oup.com/nar/article/45/14/8282/3844760 Considering that the structure of these caps is really different than the 7MeG based caps of eukaryotes, it might be undesirable to have the genes of cap binding complexes from E. coli and from eukaryotes annotated to the same term.

[bmeldal]

I have recently curated the CBCs. Yes, they are specific to RNAs but not mRNAs and I had to annotate to both terms, mRNA and nuclear CBC. And yes, the CBC is - among a host of other functions - involved in RNA export from the nucleus and functional in the cytoplasm, e.g. during pioneering round of translation.

https://www.ebi.ac.uk/complexportal/complex/search?query=cbc&page=1

I haven't yet curated the cytoplasmic cap-binding complex eIF4F that replaces CBC during translation.

[pgaudet]

@bmeldal we also have 'eukaryotic translation initiation factor 4F complex' for eIF4F; do we really need GO:0034519 cytoplasmic RNA cap binding complex ? I would propose to also obsolete that.

[pgaudet]

With @valwood's proposed changes, this is what this part of the ontology now looks like

I propose to also get rid of GO:0034519 cytoplasmic RNA cap binding complex (0 annotations). Thanks, Pascale

[pgaudet]

(In case we decide to obsolete GO:0005845 mRNA cap binding complex

• There are mappings to IPR031456 and IPR028271
• • 61 manual annotations (EXP + ISS)

[bmeldal]

There are 2 alternative translation initiation processes that require alternative cap-binding complexes:

CBC-dependent translation initiation:

1. (classic) nuclear cap-binding complex, also known as CBC or CBP20-CBP80 complex, usually composed of NCBP1 & NCBP2. https://www.ebi.ac.uk/complexportal/complex/CPX-1427 GO:0005846 nuclear cap binding complex

2. alternative nuclear cap-binding complex, usually composed of NCBP1 & NCBP3. https://www.ebi.ac.uk/complexportal/complex/CPX-3624 annotated to GO:0005846 nuclear cap binding complex

CBC binds most RNAs in the nucleus (the alternative form has a restricted repertoire of substrates) and facilitates their export into the cytoplasm.

or eIF4E-dependent translation initiation:

3. eukaryotic translation initiation factor 4F complex, also known as cytoplasmic cap-binding complex or eIF4F complex, usually consisting of eIF4E, eIF4A and eIF4G. https://www.ebi.ac.uk/complexportal/complex/CPX-430 https://www.ebi.ac.uk/complexportal/complex/CPX-431 [2 yeast variants] GO:0016281 eukaryotic translation initiation factor 4F complex

However, while it has been demonstrated that CBC binds RNA in the nucleus, the papers I have look at so far for eIF4E (and I have not exhausted that yet!) assume it binds the RNA in the cytoplasm. Hence, many papers/reviews (e.g. 23804756-F6, 24354960-F4) describe the process as a successive one where CBC is replaced by eIF4E. However, review 28088948-F1 describes the 2 processes as independent, 20094052 has a nice figure (F1) for eIF4E-dep TI but doesn't include CBC.

In any case, once in the cytoplasm, the 43S ribosomal preinitiation complex, that includes eIF3 complex, binds either cap-binding complex and the RNA.

4. Going by the def [A protein complex found in the cytoplasm that binds the 5' cap structure of an mRNA, and typically consists of the cap-binding protein eIF4E, the adaptor protein eIF4G, and a multi-factor complex comprising eIF1, eIF2, eIF3 and eIF5. This complex mediates recruitment of the 40S subunit to mRNA. PMID:16405910] GO:0034519 cytoplasmic RNA cap binding complex appear to be a supercomplex, consisting of

• GO:0016281 eukaryotic translation initiation factor 4F complex
• GO:0005852 eukaryotic translation initiation factor 3 complex
• 40S ribosomal subunit

5. GO:0098745 Dcp1-Dcp2 complex [Def: A protein complex consisting of a Dcp1 regulatory subunit and a Dcp2 catalytic subunit that has mRNA cap binding activity and is involved in decapping of nuclear-transcribed mRNA. PMID:22323607] https://www.ebi.ac.uk/complexportal/complex/CPX-1628 seems to be involved in the decapping of the RNA to ready it for degradation. It may have cap-binding properties but I wouldn't call it cap-binding complex as that name is reserved for the translation initiation complexes.

Therefore, I think there are only 2 "true" cap-binging complexes, the CBC (pts 1&2) and eIF4E (p3). I wouldn't distinguish between nuclear and cytoplasmic versions in the ontology as our knowledge may be incomplete on eIF4E.

You could add Dcp1-Dcp2 complex, but its role is the opposite to the other 2 (degradation vs translation initiation).

As for GO:0034519 cytoplasmic RNA cap binding complex - I don't think that's a true complex, it's an assembly intermediate for the assembly of the fully active ribosome!

My 2p, and I have to shoot off!

Birgit

[ValWood]

sounds sensible

• happy for Dcp2-Dcp1 mRNA-decapping complex not to be a "cap binding complex"

• We have already discussed (lots) removing location specific versions of the same complex, so this part would also be in agreement with existing proposals.

[ValWood]

I wondered which was my oldest ticket. This one by a long way. I think we could just close this. Its mainly now about nuclear vs. cytoplasmic versions of the same complex. Note- for these mRNA cap complexes I. think there are nuclear and cytoplasmic versions. Anyway I have not noticed any issues recently and I'm sure there have been subsequent tickets. Closing..... yay!

[pgaudet]

~Should I not merge into mRNA cap binding complex ?~

[pgaudet]

(1) pre-mRNA cap binding complex; components: CBP20 and CBP80 => change label to CBC cap binding complex (2) mRNA cap binding complex ; components: cap-binding protein eIF4E, the adaptor protein eIF4G, and a multi-factor complex comprising eIF1, eIF2, eIF3 and eIF5.

[pgaudet]

• [x] GO:0034519 cytoplasmic RNA cap binding complex > no annotations. Merge into GO:0005846 (renamed CBC cap binding complex)

[pgaudet]

• [x] GO:0106095 m7G(5')pppN diphosphatase complex (no annotations) > merge into GO:0098745 Dcp1-Dcp2 complex GO:0106095 corresponds to a paper describing the human version of Dcp1-Dcp2 complex.

NOTE that Dcp1-Dcp2 complex is inactive; Dcp2 is the inhibitory subunit.

Similarly, "DcpS is an 80 kDa homo-dimeric enzyme. In PMID:26258763 the human complex has been crystallized in its ligand free form and in the presence of minimal cap substrates (e.g. m7GpppG) as well as in complex with pharmaceutically relevant inhibitors".

• [x] Removed ''capable of part of' some 'deadenylation-independent decapping of nuclear-transcribed mRNA'' - since the complex is inactive; this is the activity of Dcp1 (yeast)/DcpS (human) alone.

[pgaudet]

@bmeldal GO:0106095 m7G(5')pppN diphosphatase complex did not exist when that ticket was created; do you agree this is the same complex as Dcp1-Dcp2 complex?

[pgaudet]

• [x] GO:0016281 eukaryotic translation initiation factor 4F complex add 'capable of GO:0098808 mRNA cap binding'
• [x] add NARROW synonym 'cytoplasmic cap-binding complex'

[pgaudet]

I propose to merge 'mRNA cap binding complex' (17 EXP) into 'RNA cap binding complex' (3 EXP). Both have been used to mean either 'CBC cap binding complex' or 'eukaryotic translation initiation factor 4F complex'

That would leave the 2 children

• 'CBC cap binding complex'
• 'eukaryotic translation initiation factor 4F complex'

OK @bmeldal @ValWood ?

[pgaudet]

• [ ] Should I also add capable of part of some translation initiation ?

[pgaudet]

I also dont like the very generic definition for 'RNA cap binding complex': 'Any protein complex that binds to a specialized RNA cap structure at any time in the lifetime of the RNA.' - this sounds like the MF definition, while in the CC we should be referring to specific complexes. This term should be to group the 2 children (and maybe have a 'do not annotate' flag).

• [ ] How about 'A protein complex that binds to an RNA cap structure to mediate RNA processing and/or translation initiation. ? (not sure it's that much better).

Thanks, Pascale

[ValWood]

seems OK. What is the fate of 'nuclear cap binding complex'? Isn't that also describing CBC?

[bmeldal]

[markdown edited]

Hi @pgaudet

Ok, I read back through this ticket and looked at what we've already curated, mainly in yeast but some in human/mouse as well.

My take:

nuclear cap-binding complex

= CBC; typical members: CBP20 and CBP80

-> "CBC cap-binding complex" makes no sense as you are saying " cap-binding complex cap-binding complex" ;-)

=> stick to GO:0005846 nuclear cap binding complex

• no action required unless you want to add any synonyms, maybe 'nuclear CBC' [EXACT]

cytoplasmic cap-binding complex

has 2 terms in GO which were already discussed above:

1. GO:0016281 eukaryotic translation initiation factor 4F complex = eIF4F = typical members: eIF4A1/A2, eIF4E, eIF4G1/G2

and

2. GO:0034519 cytoplasmic RNA cap binding complex - which has no annotations and is a supercomplex/assembly step for the 43S ribosomal particle made up of (see above)

• GO:0016281 eukaryotic translation initiation factor 4F complex
• GO:0005852 eukaryotic translation initiation factor 3 complex
• 40S ribosomal subunit

Suggestions:

• obsolete GO:0034519 cytoplasmic RNA cap binding complex

• keepGO:0016281 eukaryotic translation initiation factor 4F complex and:

  • add parent is_a GO:0034518 RNA cap binding complex
  • add synonym "cytoplasmic cap-binding complex" [EXACT]

NB:

GO:0034519 cytoplasmic RNA cap binding complex > no annotations. Merge into GO:0005846 (renamed CBC cap binding complex)

No, cytoplasmic CBC = eIF4F - NOT = GO:0005846 nuclear cap binding complex = CBP20-CBP80

GO:0098745 Dcp1-Dcp2 complex (= CPX-1628) and GO:0106095 m7G(5')pppN diphosphatase complex (= CPX-1179, DCS1 dimer)

• match with our CP curation and I think are different complexes:

  • Dcp1-Dcp2 decaps the mRNA while

  • DCS1 degrades the cap once removed from the mRNA (but the CP name is misleading!).

rename GO:0098745 Dcp1-Dcp2 complex "RNA decapping complex"

• I agree.

GO:0005845 mRNA cap binding complex

• I think this one can be merged with GO:0034518 RNA cap binding complex (grouping term for all the above!), at least by definition.

I think that's it!

[bmeldal]

* [ ] Should I also add capable of part of some translation initiation ?

Yes, sounds fair. I would put it on the parent term GO:0034518 RNA cap binding complex

[bmeldal]

I also dont like the very generic definition for 'RNA cap binding complex': 'Any protein complex that binds to a specialized RNA cap structure at any time in the lifetime of the RNA.' - this sounds like the MF definition, while in the CC we should be referring to specific complexes. This term should be to group the 2 children (and maybe have a 'do not annotate' flag).

* [ ]   How about 'A protein complex that binds to an RNA cap structure to mediate RNA processing and/or translation initiation. ?
  (not sure it's that much better).

Thanks, Pascale

Happy with that.

[bmeldal]

Apologies, @pgaudet I think I proposed some of your already proposed merges while getting my head around it all so I think on many things we agree. But a few things not (yet ;-) ).

[krchristie]

Since the two RNA cap structures I know of have different structures, should we specify which type of cap structure is being bound?

[ValWood]

My oldest ticket, so close to closure (a few times!)

[ValWood]

@sjm41 @pgaudet you have been looking at these activities recently. Maybe can get this ticket over the line. I'm not sure what is outstanding.

[pgaudet]

Making changes suggested by Brigit : https://github.com/geneontology/go-ontology/issues/12853#issuecomment-734850916

• [x] GO:0005846 nuclear cap binding complex : Added synonym, maybe 'nuclear CBC' [EXACT]
• [x] GO:0016281 eukaryotic translation initiation factor 4F complex: add parent is_a GO:0034518 RNA cap binding complex
• [x] add synonym "cytoplasmic cap-binding complex"
• [x] rename GO:0098745 Dcp1-Dcp2 complex "RNA decapping complex"
• [x] Update definition RNA cap binding complex': 'A protein complex that binds to an RNA cap structure to mediate RNA processing and/or translation initiation.
• [x] Obsolete GO:0034519 cytoplasmic RNA cap binding complex (no annotations) & replace by GO:0016281 eukaryotic translation initiation factor 4F complex
• [x] GO:0016281 eukaryotic translation initiation factor 4F complex: add new reference: PMID:32883864
• [ ] Obsolete GO:0005845 mRNA cap binding complex & replace by GO:0034518 RNA cap binding complex (grouping term for all the above!), at least by definition.

[pgaudet]

I will not do

Obsolete GO:0005845 mRNA cap binding complex & replace by GO:0034518 RNA cap binding complex (grouping term for all the above!), at least by definition.

because there are annotations to other enzymes, such as decapping enzymes (https://amigo.geneontology.org/amigo/reference/PMID:28533364 - PomBase @ValWood )

Maybe this will need more clean up later

[ValWood]

OK