Closed gocentral closed 9 years ago
gocentral
commented
10 years ago Original comment by: paolaroncaglia
gocentral
commented
10 years ago Add: the dimerization issue:
I just spoke to Steve and the short of it is that most GPCRs are described as monomers except for the GABA and calcitonin(-related) receptors that are OBLIGATE dimers (or more, see above). However, there is a lot of thought that the so-called monomeric receptors may in fact dimerise, either with itself or with another, possibly 'orphan', receptor (orphan receptors are those for which no ligands/G-proteins have been identified yet). Hence, I have to leave it to you whether you keep the 'dimeric' terms as it's not the 'be all or and all' situation. The only differentiation that would make sense, at least in the CC class, would be to group the aforementioned obligate dimers.
Birgit
Original comment by: bmeldal
gocentral
commented
10 years ago Hi Birgit,
Looking at this more carefully, and based on these bits in the abstracts of the references you provided:
"The 'calcitonin family' is a group of peptide hormones that share structural similarities with calcitonin, and includes calcitonin gene-related peptide (CGRP), amylin, adrenomedullin and adrenomedullin 2 (intermedin)." "The calcitonin family of peptides comprises calcitonin, amylin, two calcitonin gene-related peptides (CGRPs), and adrenomedullin."
I think the term names would best reflect this if we had:
calcitonin family receptor activity with children calcitonin receptor activity amylin receptor activity calcitonin gene-related peptide receptor activity (not 'polypeptide', see below) adrenomedullin receptor activity
I think this would be less confusing than the naming you propose:
calcitonin-related peptide receptor activity with children calcitonin gene-related polypeptide receptor activity, etc.
If you agree with this, I'll go ahead, and will check where the existing terms should be placed. As for your question: "What is the difference between ‘peptide’ and ‘polypeptide’? We should be consistent and use the alternative term as synonyms!" We go by ChEBI, where 'peptide' is the generic parent term for oligopeptide and polypeptide; here are the defs:
peptide (CHEBI:16670): Amide derived from two or more amino carboxylic acid molecules (the same or different) by formation of a covalent bond from the carbonyl carbon of one to the nitrogen atom of another with formal loss of water. The term is usually applied to structures formed from α-amino acids, but it includes those derived from any amino carboxylic acid. X = OH, OR, NH2, NHR, etc.
polypeptide (CHEBI:15841): A peptide containing ten or more amino acid residues.
So while it may be more specific to call the calcitonin gene-related thing a polypeptide than a peptide, 'peptide' is correct and the one used in the literature as far as I can tell, so I'd keep that.
Hope this all makes sense, thanks,
Paola
Original comment by: paolaroncaglia
gocentral
commented
10 years ago Hi Paola,
I agree with you on both points! Please amend the term names and thank you for enlightening me about the diff between peptide and polypeptide! I had never thought of consulting ChEBI...
Birgit
Original comment by: bmeldal
gocentral
commented
10 years ago Hi Birgit,
I started with the MF branch:
Added new terms:
1) GO:0097642 calcitonin family receptor activity is_a G-protein coupled peptide receptor activity GO:0008528 Combining with any member of the calcitonin family (e.g. adrenomedullin, adrenomedullin 2 (intermedin), amylin, calcitonin and calcitonin gene-related peptides (CGRPs)) to initiate a change in cell activity. PMID: 18687416, 10871296, 12037140 GOC:bhm InterPro:IPR003287
2) GO:0097643 amylin receptor activity is_a GO:new calcitonin family receptor activity Combining with amylin to initiate a change in cell activity. PMID: 18687416, 10871296, 12037140 GOC:bhm
Edited existing terms:
1) GO:0001635 calcitonin gene-related polypeptide receptor activity (placed under GO:new calcitonin family receptor activity; made 'calcitonin gene-related peptide receptor activity' the primary name - kept old one as exact synonym; added "CGRP" in def)
2) GO:0004948 calcitonin receptor activity (placed under GO:new calcitonin family receptor activity; alerted RGD that their annotation to Calcrl (Q63118) might best be moved to GO:0001635 calcitonin gene-related polypeptide receptor activity)
3) GO:1990407 calcitonin-gene-related polypeptide binding (made 'calcitonin gene-related peptide binding' the primary name; kept old one as exact synonym)
4) GO:1990408 calcitonin-gene-related polypeptide receptor signaling pathway (made 'calcitonin gene-related peptide receptor signaling pathway' the primary name; kept old one as exact synonym)
5)
GO:0001605 adrenomedullin receptor activity
(placed under GO:new calcitonin family receptor activity)
More soon... Cheers Paola
Original comment by: paolaroncaglia
gocentral
commented
10 years ago Also, added new terms:
GO:0097644 calcitonin family binding is_a peptide hormone binding Interacting selectively and non-covalently with any member of the calcitonin family (e.g. adrenomedullin, adrenomedullin 2 (intermedin), amylin, calcitonin and calcitonin gene-related peptides (CGRPs)). PMID: 18687416, 10871296, 12037140 GOC:bhm InterPro:IPR021116
GO:0097645 amylin binding is_a calcitonin family binding Interacting selectively and non-covalently with amylin. PMID: 18687416, 10871296, 12037140 GOC:bhm
Placed the following existing terms under GO:0097644 calcitonin family binding:
GO:1990409 adrenomedullin binding GO:1990407 calcitonin gene-related peptide binding GO:0032841 calcitonin binding
BP terms up next.
Original comment by: paolaroncaglia
gocentral
commented
10 years ago Hi Birgit,
As for your question:
"[i] dimeric G-protein coupled receptor signaling pathway GO:0038042 [Do we need this ‘dimeric’ child of the GPCR signaling pathway term? There are tonnes of GPCR signaling pathway terms but only one that defines stoichiometry (also see below for complex terms). I’m no expert in GPCR signaling…]"
The def. of dimeric G-protein coupled receptor signaling pathway GO:0038042 says: "A series of molecular signals initiated by an extracellular signal combining with a dimeric receptor on the surface of the target cell, and proceeding with the activated receptor promoting the exchange of GDP for GTP on the alpha-subunit of an associated heterotrimeric G-protein complex. Heterodimeric and homodimeric GPCRs may have different functional properties from those of the respective monomers." So I think yes, it's good to have a specific term. Receptor properties being different may well reflect on the whole pathway. But I'm no expert either. If you're still not convinced, I'll ask Becky, who created that term.
Thanks, Paola P.S. Re-reading your further comments on this issue, I still think we could leave the term as is... it adds specificity. If we don't know if a pathway is initiated by a [stoichiometry x] receptor, with or without orphan receptors, it's still fine to place the pathway under a generic GPCR term - it's not wrong. My 2 pence.
Original comment by: paolaroncaglia
gocentral
commented
10 years ago BP branch: Added new terms:
1) GO:0097646 calcitonin family receptor signaling pathway is_a dimeric G-protein coupled receptor signaling pathway A series of molecular signals initiated by an extracellular member of the calcitonin family (e.g. adrenomedullin, adrenomedullin 2 (intermedin), amylin, calcitonin and calcitonin gene-related peptides (CGRPs)) combining with a dimeric calcitonin family receptor on the surface of the target cell. PMID: 18687416, 10871296, 12037140, GOC:bhm exact synonym: calcitonin family receptor signalling pathway
2) GO:0097647 amylin receptor signaling pathway is_a GO:0097646 calcitonin family receptor signaling pathway A series of molecular signals initiated by an extracellular amylin combining with a dimeric amylin receptor on the surface of the target cell. PMID: 18687416, 10871296, 12037140, GOC:bhm exact synonym: amylin receptor signalling pathway
Placed these existing terms under GO:0097646 calcitonin family receptor signaling pathway:
adrenomedullin receptor signaling pathway GO:1990410 calcitonin gene-related peptide receptor signaling pathway GO:1990408
Original comment by: paolaroncaglia
gocentral
commented
9 years ago Hi again Birgit,
Added new term: GO:0097648 G-protein coupled receptor complex is_a receptor complex part_of integral component of plasma membrane A protein complex that contains G-protein coupled receptors. GOC:bhm
Placed 'G-protein coupled receptor dimeric complex' under GO:0097648 G-protein coupled receptor complex
As for your request: "calcitonin-related peptide receptor complex GO:NEW ---[i] G-protein coupled receptor heterodimeric complex GO:0038039 [or whatever we replace it with]" I'm not sure I gathered this from your discussion on receptor dimers: are the receptors for members of the calcitonin family ALWAYS paired as heterodimers? Or are they sometimes homodimers, sometimes heterodimers and sometimes dimers of a calcitonin family receptor with an orphan receptor? If the latter is true, or if we don't have certainty that the former is ALWAYS true, then I'd place GO:NEW 'calcitonin family receptor complex' as is_a more generic 'G-protein coupled receptor dimeric complex'.
Based on your response, I'll create 'calcitonin family receptor complex' and add/edit its children.
Thanks, Paola
Original comment by: paolaroncaglia
gocentral
commented
9 years ago Hi Paola,
I checked again what I said about the stoichiometry: calcitonin-related GPCRs are thought to be dimeric but the calcitonin receptor itself is monomeric (as far as it is known). Therefore, any calcitonin terms (binding, receptor activity, signaling pathway) cannot be children of the specific 'dimeric' parent terms. So:
from you:
A) ""[i] dimeric G-protein coupled receptor signaling pathway GO:0038042 [Do we need this ‘dimeric’ child of the GPCR signaling pathway term? There are tonnes of GPCR signaling pathway terms but only one that defines stoichiometry (also see below for complex terms). I’m no expert in GPCR signaling…]"
The def. of dimeric G-protein coupled receptor signaling pathway GO:0038042 says: "A series of molecular signals initiated by an extracellular signal combining with a dimeric receptor on the surface of the target cell, and proceeding with the activated receptor promoting the exchange of GDP for GTP on the alpha-subunit of an associated heterotrimeric G-protein complex. Heterodimeric and homodimeric GPCRs may have different functional properties from those of the respective monomers." So I think yes, it's good to have a specific term. Receptor properties being different may well reflect on the whole pathway. But I'm no expert either. If you're still not convinced, I'll ask Becky, who created that term."
AND
B) "As for your request: "calcitonin-related peptide receptor complex GO:NEW ---[i] G-protein coupled receptor heterodimeric complex GO:0038039 [or whatever we replace it with]" I'm not sure I gathered this from your discussion on receptor dimers: are the receptors for members of the calcitonin family ALWAYS paired as heterodimers? Or are they sometimes homodimers, sometimes heterodimers and sometimes dimers of a calcitonin family receptor with an orphan receptor? If the latter is true, or if we don't have certainty that the former is ALWAYS true, then I'd place GO:NEW 'calcitonin family receptor complex' as is_a more generic 'G-protein coupled receptor dimeric complex'.
Based on your response, I'll create 'calcitonin family receptor complex' and add/edit its children."
AND
C) " GO:0097646 calcitonin family receptor signaling pathway is_a dimeric G-protein coupled receptor signaling pathway A series of molecular signals initiated by an extracellular member of the calcitonin family (e.g. adrenomedullin, adrenomedullin 2 (intermedin), amylin, calcitonin and calcitonin gene-related peptides (CGRPs)) combining with a dimeric calcitonin family receptor on the surface of the target cell. PMID: 18687416, 10871296, 12037140, GOC:bhm exact synonym: calcitonin family receptor signalling pathway"
--> take out calcitonin in above def (C) as it doesn't combine with dimeric GPCR. [There is no calcitonin receptor signaling pathway term to capture the calcitonin branch itself, neither is there a term for calcitonin receptor complex]
--> it also makes it difficult to name the terms 'calcitonin family X...' as the InterPro family includes calcitonin but the terms won't... Tricky. Another reason why we need to be careful with the 'dimeric' in the terms/defs.
Sorry to add to the confusion!
Birgit
Original comment by: bmeldal
gocentral
commented
9 years ago Hi Birgit,
Thanks. I looked at all terms containing 'calcitonin' in their primary name and I did the following:
calcitonin family receptor signaling pathway:
Note that children of 'calcitonin family receptor signaling pathway' could be added the is_a parent 'dimeric G-protein coupled receptor signaling pathway' without breaking anything, but you write that "calcitonin-related GPCRs are thought to be dimeric", which I interpret as "there is no absolute certainty that calcitonin-related GPCRs are dimeric". If, however, the interpretation should rather be: "as of today, there is no evidence or reason to believe that calcitonin-related GPCRs are not dimeric", then I will make the 3 terms 'adrenomedullin/amylin/calcitonin gene-related peptide receptor signaling pathway' is_a 'dimeric G-protein coupled receptor signaling pathway'. Let me know. :-) Note that the current defs. of those 3 terms say 'dimeric' but that might have been my mistake. So depending on your reply, I may have to remove that 'dimeric' from those 3 defs.
Placement of all other calcitonin terms looks ok to me.
Cheers, Paola
Original comment by: paolaroncaglia
gocentral
commented
9 years ago I double-checked the existing evidence: The receptors with the CGRPs may be trimers or tetramers with one or both dimer units dimeric themselves but the evidence is still quite weak. So at least for these, we should not put them under the 'dimeric' parent terms, but the AM and amylin receptors have so far only been shown to be dimeric.
Are we ever absolutely sure about anything ;-)
Birgit
Original comment by: bmeldal
gocentral
commented
9 years ago Thanks Birgit. Done the following edits:
calcitonin family receptor signaling pathway:
adrenomedullin receptor signaling pathway:
amylin receptor signaling pathway:
calcitonin gene-related peptide receptor signaling pathway:
Original comment by: paolaroncaglia
gocentral
commented
9 years ago Hi again Birgit,
for the CC terms, the structure is now:
calcitonin family receptor complex [NEW] ---adrenomedullin receptor complex [edited] ---amylin receptor complex [NEW] ---CGRP receptor complex [edited]
In more detail, the full ontology stanzas for these terms are below (resulting from a combination of TG creation and OBO-editing):
[Term] id: GO:1903439 name: calcitonin family receptor complex namespace: cellular_component def: "A protein complex which is capable of calcitonin family receptor activity. Calcitonin family receptors may form dimers, trimers or tetramers; adrenomedullin and amylin receptors have only been observed as dimers so far." [GO_REF:0000088, GOC:bhm, GOC:TermGenie, PMID:10871296, PMID:12037140, PMID:18687416] is_a: GO:0097648 ! G-protein coupled receptor complex intersection_of: GO:0043234 ! protein complex intersection_of: capable_of GO:0097642 ! calcitonin family receptor activity relationship: capable_of GO:0097642 {is_inferred="true"} ! calcitonin family receptor activity
[Term] id: GO:1903143 name: adrenomedullin receptor complex namespace: cellular_component def: "A transmembrane, G-protein-coupled signalling receptor complex which is capable of adrenomedullin receptor activity." [GO_REF:0000088, GOC:bhm, GOC:TermGenie, PMID:22102369] comment: An example of this is RAMP2 in human (O60895) in PMID:22102369 (inferred from direct assay). synonym: "adrenomedullin receptor AM1 complex" NARROW [] synonym: "adrenomedullin receptor AM2 complex" NARROW [] is_a: GO:0038037 ! G-protein coupled receptor dimeric complex is_a: GO:1903439 {is_inferred="true"} ! calcitonin family receptor complex intersection_of: GO:0043234 ! protein complex intersection_of: capable_of GO:0001605 ! adrenomedullin receptor activity relationship: capable_of GO:0001605 {is_inferred="true"} ! adrenomedullin receptor activity
[Term] id: GO:1903440 name: amylin receptor complex namespace: cellular_component def: "A protein complex which is capable of amylin receptor activity." [GO_REF:0000088, GOC:bhm, GOC:TermGenie, PMID:10871296, PMID:12037140, PMID:18687416] is_a: GO:1903439 ! calcitonin family receptor complex intersection_of: GO:0043234 ! protein complex intersection_of: capable_of GO:0097643 ! amylin receptor activity relationship: capable_of GO:0097643 {is_inferred="true"} ! amylin receptor activity
[Term] id: GO:1990406 name: CGRP receptor complex namespace: cellular_component def: "A transmembrane, G-protein-coupled signalling receptor complex recognized by calcitonin gene-related peptides (CGRP)." [GOC:bhm, IntAct:EBI-9009008, PMID:20826335] comment: An example of this is CALCRL in human (Q16602) in PMID:20826335 (inferred from direct assay). synonym: "calcitonin gene-related polypeptide receptor complex" EXACT [] synonym: "Calcitonin-gene-related peptide receptor complex" EXACT [] synonym: "CGRP-R complex" EXACT [] is_a: GO:0038037 ! G-protein coupled receptor dimeric complex is_a: GO:1903439 {is_inferred="true"} ! calcitonin family receptor complex intersection_of: GO:0043234 ! protein complex intersection_of: capable_of GO:0001635 ! calcitonin gene-related peptide receptor activity relationship: capable_of GO:0001635 ! calcitonin gene-related peptide receptor activity relationship: part_of GO:0005887 ! integral component of plasma membrane
Original comment by: paolaroncaglia
gocentral
commented
9 years ago I think this request has been fulfilled and I'm closing the ticket :-) But feel free to re-open in case I forgot anything or if you have any concerns. Cheers, Paola
Original comment by: paolaroncaglia
gocentral
commented
9 years ago Original comment by: paolaroncaglia
gocentral
commented
9 years ago Hi Paola,
Thanks you for all the new terms!
I think we have the amylin and CGRP receptors complex defs muddled up:
[Term] id: GO:1903440 name: amylin receptor complex namespace: cellular_component def: "A protein complex which is capable of amylin receptor activity." [GO_REF:0000088, GOC:bhm, GOC:TermGenie, PMID:10871296, PMID:12037140, PMID:18687416] is_a: GO:1903439 ! calcitonin family receptor complex
--> ADD: is_a: GO:0038037 ! G-protein coupled receptor dimeric complex
BECAUSE: "adrenomedullin and amylin receptors have only been observed as dimers so far." see above for adrenomedullin receptor
intersection_of: GO:0043234 ! protein complex intersection_of: capable_of GO:0097643 ! amylin receptor activity relationship: capable_of GO:0097643 {is_inferred="true"} ! amylin receptor activity
[Term] id: GO:1990406 name: CGRP receptor complex namespace: cellular_component def: "A transmembrane, G-protein-coupled signalling receptor complex recognized by calcitonin gene-related peptides (CGRP)." [GOC:bhm, IntAct:EBI-9009008, PMID:20826335] comment: An example of this is CALCRL in human (Q16602) in PMID:20826335 (inferred from direct assay). synonym: "calcitonin gene-related polypeptide receptor complex" EXACT [] synonym: "Calcitonin-gene-related peptide receptor complex" EXACT [] synonym: "CGRP-R complex" EXACT []
--> DELETE: is_a: GO:0038037 ! G-protein coupled receptor dimeric complex
BECAUSE: "Calcitonin family receptors may form dimers, trimers or tetramers; adrenomedullin and amylin receptors have only been observed as dimers so far."
is_a: GO:1903439 {is_inferred="true"} ! calcitonin family receptor complex intersection_of: GO:0043234 ! protein complex intersection_of: capable_of GO:0001635 ! calcitonin gene-related peptide receptor activity relationship: capable_of GO:0001635 ! calcitonin gene-related peptide receptor activity relationship: part_of GO:0005887 ! integral component of plasma membrane
We can also add
relationship: part_of GO:0005887 ! integral component of plasma membrane
to all 4 terms!
Thanks, Birgit
Original comment by: bmeldal
gocentral
commented
9 years ago Sorry Birgit, something got muddled up. Last edits:
calcitonin family receptor complex:
amylin receptor complex:
CGRP receptor complex:
Cheers! Paola
Original comment by: paolaroncaglia
Hi (Paola?),
sorry, this is am long one!
I’ve been making several new GPCR related complexes and noticed some holes and inconsistencies in the GO. The main problem lies in the CC branch but I will need new MF and BP terms so I can make the logical definitions for the new CC terms.
I’m proposing a new set of parent terms for my new terms: calcitonin-related peptide… [activity/binding/pathway/complex]. ‘calcitonin-related gene product’, amylin and adrenomedullin are all calcitonin-related peptides. Their receptors are all structurally (as far as known) and functionally similar, with cross-reactivity in some cases. Receptors are named by their main ligand. You may notice that I haven’t included ‘calcitoning receptor…’ terms: that’s because the calcitonin receptor itself is monomeric and therefore out of my scope (of building complexes)!
If you agree with my suggestions, I will create all the new terms in TermGenie. But before I create a mess, I thought I’d gather opinions first :) Plus, some points are corrections which I couldn’t do myself anyway. [indicated in parenthesis]
The defs for the new terms are self-evident from their sibling/parent/child terms, I won’t type them all out here!
The CC terms will all get the relevant capable_of and capable_of_part_of definitions when building them but of course I will need the new MF and BP terms first. I’m sure some of the existing CC terms are also missing the extensions but I can’t see them from my end.
Relevant PMID: 18687416, 10871296, 12037140 (for the calcitonin-related and, in particular, amylin complexes) Another note: for most of these complexes evidence is pharmacological rather than from direct binding assays (esp the amylin receptors). These complexes were direct submissions from ChEMBL to the Complex Portal. Some crystal structures exist (for parts of the CRGP and adrenomedullin 1 complexes. I created those terms a short while ago and are included in the revised hierarchies below).
In case it is useful (certainly for me!), I made some ppt slides with graphical representations of the changes required. Comments are in red speech bubbles.
Here it goes:
MF activity terms:
calcitonin-related peptide receptor activity GO:NEW ---[i] G-protein coupled receptor activity GO:0008528
amylin receptor activity GO:NEW adrenomedullin receptor activity GO:0001605 [correction] calcitonin gene-related polypeptide receptor activity GO:0001635 [correction] all: --- [i] calcitonin-related peptide receptor activity GO:NEW
[NB: What is the difference between ‘peptide’ and ‘polypeptide’? We should be consistent and use the alternative term as synonyms!]
MF binding terms:
calcitonin-related peptide binding GO:NEW ---[i] peptide binding GO:0042277
amylin binding GO:NEW adrenomedullin binding GO:1990409 [correction] calcitonin gene-related polypeptide binding GO:1990407 [correction] all: --- [i] calcitonin-related peptide binding GO:NEW
BP terms:
calcitonin-related peptide receptor signaling pathway GO:NEW ---[i] dimeric G-protein coupled receptor signaling pathway GO:0038042
[Do we need this ‘dimeric’ child of the GPCR signaling pathway term? There are tonnes of GPCR signaling pathway terms but only one that defines stoichiometry (also see below for complex terms). I’m no expert in GPCR signaling…]
amylin receptor signaling pathway GO:NEW adrenomedullin receptor signaling pathway GO:1990410 [correction] calcitonin gene-related polypeptide receptor signaling pathway GO:1990408 [correction] all: --- [i] calcitonin-related peptide receptor signaling pathway GO:NEW
CC complex terms:
G-protein coupled receptor dimeric complex GO:0038037: This seems to be a bit of a ‘lonely’ term. For starters, there is no parent. So we need:
G-protein coupled receptor complex GO:NEW [or adjust the name and def and remove the ‘dimeric’, see below.]
Also, as remarked above, most of the other GPCR related terms don’t mention any stoichiometry but there are a lot of BP terms as siblings to a dimeric GPCR pathway. Since many GPCRs are monomeric I assume most of the GPCR terms refer to the monomeric receptors. Should we make ‘monomeric GPCR receptor xxx’ terms or just do away with the ‘dimeric’ terms? It seems inconsistent and I thought generally, the GO does not distinguish by stoichiometry. The ones I’m doing right now seem to be dimeric but there is some vague evidence that some may have a 2:1 or 2:2 structure… I’d be happy with excluding the whole stoichiometry from the parent terms. If a specific receptor ALWAYS occurs as a dimer we should just mention it in the def.
As I said above, I’m no expert in GPCR signalling. Our resident expert on GPCRs is away til Monday but I can ask him then.
Specific terms:
calcitonin-related peptide receptor complex GO:NEW ---[i] G-protein coupled receptor heterodimeric complex GO:0038039 [or whatever we replace it with]
amylin receptor complex GO:NEW adrenomedullin receptor complex GO:1990413 [correction] calcitonin gene-related polypeptide receptor complex GO:1990406 [correction] all: --- [i] calcitonin-related peptide receptor signaling pathway GO:NEW
Related: Are all receptor complexes membrane bound? Maybe not.
However, G-protein coupled receptor dimeric complex GO:0038037 should be --- [p] integral component of plasma membrane GO:0005887 [correction] [having 7 transmembrane domains by definition I can’t imagine any GPCRs are not membrane bound]
Thank you for your patience and making it to the end, Birgit
Reported by: bmeldal
Original Ticket: geneontology/ontology-requests/11057