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Curator prediction of NOT kinase activity

Karen Pilcher kpilcher at northwestern.edu
Wed Mar 8 07:07:18 PST 2006


Also sorry to chime in late here...

We have annotated all the kinases in dictyBase in collaboration with a lab 
(manuscript in press).  We identified a number of kinases that lacked 
critical residues, and in those cases we annotated to 
'molecular_function_unknown.'

 From PMID 12471243 (human kinome paper):

"nearly 10% of all
kinase domains appear to lack catalytic activity.
However, these domains are otherwise well
conserved and are likely to maintain the typical
kinase domain fold. This suggests that this domain
can have generalized noncatalytic functions;
it is also possible that they use a modified
catalytic mechanism that does not require these
residues. This has been shown for the Wnk
family, where Lys13 is thought to replace Lys30
in adenosine triphosphate (ATP) binding (25)."

In other words, nobody knows what they do, so we annotated to 'unknown' 
since we were uncomfortable with 'protein kinase activity.'

Karen


At 07:54 AM 3/8/2006, Alexander D. Diehl wrote:
>Hi,
>
>Sorry to be so late on this discussion, but I would like suggest that 
>perhaps the annotation is inappropriate on the grounds that NOT 
>annotations in general are very tricky assertions, and are best based on 
>actual experimental evidence, which itself is very dependent on the 
>experimental conditions used.  There's a universe of proteins that I could 
>provide NOT kinase activity for, but of course most people would not 
>confuse them with kinases.  The question here is more whether the original 
>algorithms for predicting kinase activity need to be refined so that 
>proteins lacking the correct residues in the active site are not flagged 
>as kinases in the first place.  Such refinement, of course, ought best to 
>be based on experimental evidence (wet science) that feeds the 
>computational algorithm development, and that's where expert input is needed.
>
>I thus vote against any annotation at all in this case.
>
>-- Alex
>
>
>Evelyn Camon wrote:
>>>what were the objections to a GO_REF, this would be unambiguous
>>
>>Hi,
>>
>>The issue of using the GO_REF vs extension of the evidence codes is on
>>the GO Consortium meeting agenda.
>>
>>Arguments against GO_REF include:
>>
>>I don't think the users will read about GO_REF (is that our problem?)
>>I don't think the users will even see GO_REF in most tools, microarray, 
>>we are also limited in UniProt ffl to 4 fields of GO information
>>Users can filter on GO_REF plus evidence code but are we simply avoiding 
>>extending the number of useful GO evidence codes, for manual codes I can 
>>see that extending the codes might slow down curation but for more 
>>granular IEA codes, they are created electronically so no extra effort 
>>from curator required.
>>Biology is complex. Although I don't like to see information lost I think 
>>we further complicate what was a simple annotation process and output.
>>
>>Arguments in favour GO_REF include:
>>
>>many different techniques not practical (or is it) to create ne evidence 
>>codes, helps to disambiguate annotations
>>
>>I am really not wishing to start a new thread here...can we leave GO_REF 
>>and codes to Consortium meeting, I am still collecting ideas..you could 
>>reply to me directly if you wish me to collect further 'for' and 
>>'aganist' examples for discussion.
>>
>>cheers
>>Evelyn
>>
>>
>>>
>>>
>>>So all annotations which use
>>>
>>>NOT with the ISS evidence code and GO_REF:xxx and a dbxref to an
>>>alignment
>>>mean that:
>>>
>>>The curator or an expert have looked at  the alignment of this sequence
>>>to the associated database entry, protein family or hmm, and on the
>>>basis of the absence of critical residues have inferred that this family
>>>member is unlikely possess the associated activity.
>>>
>>>Or words to that effect.
>>>
>>>
>>>
>>>David Hill wrote:
>>>
>>>>I can see your point, but that would mean that every database should
>>>>have an internal ISS reference. We have one, but it is only for
>>>>orthology and subsequent inheritence of GO terms. Our's doesn't address
>>>>this issue of a NOT. I think in either case, a User might be confused.
>>>>If I were a naive User and I saw the annotation as you describe, I might
>>>>think the NOT was a mistake becasue the proteins were so similar. If the
>>>>protein in the with field is taken from the paper that discusses the
>>>>critical residues, then maybe it would be less confusing. I'm not sure.
>>>>I think we could generate confusion both ways.
>>>>
>>>>David
>>>>
>>>>Pascale Gaudet wrote:
>>>>
>>>>
>>>>>Hi,
>>>>>
>>>>>Is this allowed? I thought that the reference had to directly relate
>>>>>to the annotation. In this case I would have used our standard
>>>>>'dictybase curators ISS' reference, because that's how the annotation
>>>>>was made.
>>>>>
>>>>>If I was to see the annotation as you describe it, I might be tempted
>>>>>to go and look at the reference, and I would be very confused because
>>>>>it doesn't talk about the protein at all.
>>>>>
>>>>>Pascale
>>>>>
>>>>>
>>>>>At 07:49 AM 3/8/2006 -0500, David Hill wrote:
>>>>>
>>>>>
>>>>>>This is a bit out of the ordinary, but what about an ISS evidence
>>>>>>code with an active kinase and then a reference to a paper that
>>>>>>identifies the critical residues for kinase activity?
>>>>>>
>>>>>>David
>>>>>>
>>>>>>Midori Harris wrote:
>>>>>>
>>>>>>
>>>>>>>Seems to me it would be a valuable part of the story, but not
>>>>>>>necessarily the whole thing. It would tell you what the important
>>>>>>>residues are, but would miss out the part about observing that those
>>>>>>>residues are altered/absent in this particular protein. Also, citing
>>>>>>>only the important-residue reference could give the impression that
>>>>>>>that paper (or whatever it is) actually states that protein XYZ
>>>>>>>doesn't have the activity -- which I assume is not the case.
>>>>>>>
>>>>>>>m
>>>>>>>
>>>>>>>On Wed, 8 Mar 2006, jyoti khadake wrote:
>>>>>>>
>>>>>>>
>>>>>>>
>>>>>>>
>>>>>>>>Hi,
>>>>>>>>
>>>>>>>>In this particular instance would the reference which identifies
>>>>>>>>residues important for the kinase activity in members of the family
>>>>>>>>be the appropriate reference?
>>>>>>>>
>>>>>>>>JK
>>>>>>>>
>>>>>>>>Midori Harris wrote:
>>>>>>>>
>>>>>>>>
>>>>>>>>
>>>>>>>>
>>>>>>>>>The reference has to identify the source of the information. In
>>>>>>>>>this case,
>>>>>>>>>it comes from what the curator knows, and from the work she did
>>>>>>>>>examining
>>>>>>>>>the protein sequence. So I don't think the protein ID would suffice,
>>>>>>>>>because it would capture nothing of the curator's involvement. The
>>>>>>>>>advantage of a GO_REF is that we could include everything the
>>>>>>>>>curator did,
>>>>>>>>>and make it unambiguous ... but it's not for me to decide whether
>>>>>>>>>that
>>>>>>>>>advantage outweighs the problems (btw, what are the arguments
>>>>>>>>>against a
>>>>>>>>>GO_REF?)
>>>>>>>>>
>>>>>>>>>m
>>>>>>>>>
>>>>>>>>>On Wed, 8 Mar 2006, Emily Dimmer wrote:
>>>>>>>>>
>>>>>>>>>
>>>>>>>>>
>>>>>>>>>
>>>>>>>>>
>>>>>>>>>>So if using the ISS code with these kinds of annotations, what
>>>>>>>>>>reference information should be provided? Should the reference
>>>>>>>>>>field refer back to the protein's identifier? Or to a specific
>>>>>>>>>>GO_REF (which isn't ideal)
>>>>>>>>>>e.g.
>>>>>>>>>>UniProt     P12345      GO:0004672      UniProt:P12345
>>>>>>>>>>ISS   F
>>>>>>>>>>protein    taxon:9606 20060308       UniProt
>>>>>>>>>>
>>>>>>>>>>Midori Harris wrote:
>>>>>>>>>>
>>>>>>>>>>
>>>>>>>>>>
>>>>>>>>>>
>>>>>>>>>>
>>>>>>>>>>
>>>>>>>>>>>The documentation for ISS says that it can be used for predicted
>>>>>>>>>>>or observed sequence features, and that in such cases the 'with'
>>>>>>>>>>>field can be left blank. If we choose to regard altered 'active'
>>>>>>>>>>>site residues as features -- which seems reasonable -- ISS will
>>>>>>>>>>>work.
>>>>>>>>>>>
>>>>>>>>>>>Also, using IC would not solve the reference problem, so you
>>>>>>>>>>>would still have to either (a) make a GO_REF entry or (b) think
>>>>>>>>>>>of something else to use as the reference.
>>>>>>>>>>>
>>>>>>>>>>>m
>>>>>>>>>>>
>>>>>>>>>>>On Wed, 8 Mar 2006, Evelyn Camon wrote:
>>>>>>>>>>>
>>>>>>>>>>>
>>>>>>>>>>>
>>>>>>>>>>>
>>>>>>>>>>>
>>>>>>>>>>>
>>>>>>>>>>>
>>>>>>>>>>>
>>>>>>>>>>>>ok..so sequence similar to what?? the sequence/domain for the
>>>>>>>>>>>>active kinase??? or could we have Inferred by Curator from
>>>>>>>>>>>>Sequence (ICS??)..hmmm
>>>>>>>>>>>>
>>>>>>>>>>>>Ev
>>>>>>>>>>>>
>>>>>>>>>>>>Valerie Wood wrote:
>>>>>>>>>>>>
>>>>>>>>>>>>
>>>>>>>>>>>>
>>>>>>>>>>>>
>>>>>>>>>>>>
>>>>>>>>>>>>
>>>>>>>>>>>>
>>>>>>>>>>>>>I think I prefer ISS, because this is essentially a judgement
>>>>>>>>>>>>>which has
>>>>>>>>>>>>>been made by assessing the sequence.....
>>>>>>>>>>>>>
>>>>>>>>>>>>>Evelyn Camon wrote:
>>>>>>>>>>>>>
>>>>>>>>>>>>>
>>>>>>>>>>>>>
>>>>>>>>>>>>>
>>>>>>>>>>>>>
>>>>>>>>>>>>>
>>>>>>>>>>>>>
>>>>>>>>>>>>>
>>>>>>>>>>>>>>Hi,
>>>>>>>>>>>>>>
>>>>>>>>>>>>>>I'm not keen on the GO_REF idea I'm afraid...could we propose
>>>>>>>>>>>>>>that IC
>>>>>>>>>>>>>>could be used without GO ID on these odd occasions...not sure
>>>>>>>>>>>>>>what
>>>>>>>>>>>>>>publication you would use though...
>>>>>>>>>>>>>>
>>>>>>>>>>>>>>Ev
>>>>>>>>>>>>>>
>>>>>>>>>>>>>>Sandra Orchard wrote:
>>>>>>>>>>>>>>
>>>>>>>>>>>>>>
>>>>>>>>>>>>>>
>>>>>>>>>>>>>>
>>>>>>>>>>>>>>
>>>>>>>>>>>>>>
>>>>>>>>>>>>>>
>>>>>>>>>>>>>>
>>>>>>>>>>>>>>>Most kinase recognition patterns are HMMs which can only
>>>>>>>>>>>>>>>predict a
>>>>>>>>>>>>>>>domain but will not tell you if it is active or not. The
>>>>>>>>>>>>>>>kinases in
>>>>>>>>>>>>>>>these examples were hit by the HMMs. The only method which
>>>>>>>>>>>>>>>will give any
>>>>>>>>>>>>>>>indication of activity are ProSite patterns which
>>>>>>>>>>>>>>>specifically say a
>>>>>>>>>>>>>>>particular residue needs to be in a particulr position. The
>>>>>>>>>>>>>>>HMMs are
>>>>>>>>>>>>>>>correct in that these are part of the kinase family, but are
>>>>>>>>>>>>>>>inactive
>>>>>>>>>>>>>>>members of it, they are not false positives in that sense.
>>>>>>>>>>>>>>>This is true
>>>>>>>>>>>>>>>for many different classes of enzyme.
>>>>>>>>>>>>>>>
>>>>>>>>>>>>>>>And I do not remove enzyme InterPro2GO annotation just
>>>>>>>>>>>>>>>because a family
>>>>>>>>>>>>>>>contains a few inactive members - all the big enzyme
>>>>>>>>>>>>>>>families do and
>>>>>>>>>>>>>>>they can only really be recognised by manual annotation.
>>>>>>>>>>>>>>>
>>>>>>>>>>>>>>>Sandra
>>>>>>>>>>>>>>>
>>>>>>>>>>>>>>>Valerie Wood wrote:
>>>>>>>>>>>>>>>
>>>>>>>>>>>>>>>
>>>>>>>>>>>>>>>
>>>>>>>>>>>>>>>
>>>>>>>>>>>>>>>
>>>>>>>>>>>>>>>
>>>>>>>>>>>>>>>
>>>>>>>>>>>>>>>
>>>>>>>>>>>>>>>
>>>>>>>>>>>>>>>>Hi Emily,
>>>>>>>>>>>>>>>>
>>>>>>>>>>>>>>>>A few comments which may be relevant:
>>>>>>>>>>>>>>>>
>>>>>>>>>>>>>>>>Out of interest, which protein kinase family is this (i.e.
>>>>>>>>>>>>>>>>which
>>>>>>>>>>>>>>>>Interpro domain). Is it a family where some (but not all)
>>>>>>>>>>>>>>>>members are
>>>>>>>>>>>>>>>>protein kinases, in
>>>>>>>>>>>>>>>>which case the mapping should be removed?
>>>>>>>>>>>>>>>>
>>>>>>>>>>>>>>>>Alternatively, if this appears to be a spurious hit,
>>>>>>>>>>>>>>>>instead of adding a
>>>>>>>>>>>>>>>>NOT annotation, you can get spurious matches suppressed by
>>>>>>>>>>>>>>>>Interpro as
>>>>>>>>>>>>>>>>false positives (I often do this for S. pombe).
>>>>>>>>>>>>>>>>
>>>>>>>>>>>>>>>>Or, could it be a sequencing or gene predicition error?
>>>>>>>>>>>>>>>>
>>>>>>>>>>>>>>>>
>>>>>>>>>>>>>>>>
>>>>>>>>>>>>>>>>Val
>>>>>>>>>>>>>>>>
>>>>>>>>>>>>>>>>
>>>>>>>>>>>>>>>>Midori Harris wrote:
>>>>>>>>>>>>>>>>
>>>>>>>>>>>>>>>>
>>>>>>>>>>>>>>>>
>>>>>>>>>>>>>>>>
>>>>>>>>>>>>>>>>
>>>>>>>>>>>>>>>>
>>>>>>>>>>>>>>>>
>>>>>>>>>>>>>>>>
>>>>>>>>>>>>>>>>
>>>>>>>>>>>>>>>>
>>>>>>>>>>>>>>>>>Hi,
>>>>>>>>>>>>>>>>>
>>>>>>>>>>>>>>>>>I think there's no doubt whatsoever that this information
>>>>>>>>>>>>>>>>>should be
>>>>>>>>>>>>>>>>>captured. The question is what to put for reference and
>>>>>>>>>>>>>>>>>evidence. The
>>>>>>>>>>>>>>>>>best
>>>>>>>>>>>>>>>>>evidence code is probably TAS, although one could possibly
>>>>>>>>>>>>>>>>>also make a
>>>>>>>>>>>>>>>>>case for ISS (note that IC is restricted to inferences
>>>>>>>>>>>>>>>>>from other GO
>>>>>>>>>>>>>>>>>annotations, so isn't suitable).
>>>>>>>>>>>>>>>>>
>>>>>>>>>>>>>>>>>For a reference, one possibility is to add an item to the
>>>>>>>>>>>>>>>>>GO_REF
>>>>>>>>>>>>>>>>>collection; then there would be an ID to plug into the file.
>>>>>>>>>>>>>>>>>
>>>>>>>>>>>>>>>>>m
>>>>>>>>>>>>>>>>>
>>>>>>>>>>>>>>>>>On Wed, 8 Mar 2006, Emily Dimmer wrote:
>>>>>>>>>>>>>>>>>
>>>>>>>>>>>>>>>>>
>>>>>>>>>>>>>>>>>
>>>>>>>>>>>>>>>>>
>>>>>>>>>>>>>>>>>
>>>>>>>>>>>>>>>>>
>>>>>>>>>>>>>>>>>
>>>>>>>>>>>>>>>>>
>>>>>>>>>>>>>>>>>
>>>>>>>>>>>>>>>>>
>>>>>>>>>>>>>>>>>
>>>>>>>>>>>>>>>>>>Hi,
>>>>>>>>>>>>>>>>>>
>>>>>>>>>>>>>>>>>>One of our annotators, who is an expert on protein
>>>>>>>>>>>>>>>>>>kinases, has looked
>>>>>>>>>>>>>>>>>>at the sequence of a putative protein kinase and from
>>>>>>>>>>>>>>>>>>noticing a couple
>>>>>>>>>>>>>>>>>>of amino acids changes at its active site, has predicted
>>>>>>>>>>>>>>>>>>that it does
>>>>>>>>>>>>>>>>>>not possess any kinase activity - she did not use any
>>>>>>>>>>>>>>>>>>software and
>>>>>>>>>>>>>>>>>>there
>>>>>>>>>>>>>>>>>>is no published work on this protein.
>>>>>>>>>>>>>>>>>>Do you think this type of annotation should be
>>>>>>>>>>>>>>>>>>represented in GO (we
>>>>>>>>>>>>>>>>>>feel this annotation is of high quality and adds valuable
>>>>>>>>>>>>>>>>>>information to
>>>>>>>>>>>>>>>>>>a protein which has not yet been characterized), and if
>>>>>>>>>>>>>>>>>>so how should
>>>>>>>>>>>>>>>>>>this annotation be shown?
>>>>>>>>>>>>>>>>>>
>>>>>>>>>>>>>>>>>>Thanks,
>>>>>>>>>>>>>>>>>>Emily
>>>>>>>>>>>>>>>>>>
>>>>>>>>>>>>>>>>>>
>>>>>>>>>>>>>>>>>>
>>>>>>>>>>>>>>>>>>
>>>>>>>>>>>>>>>>>>
>>>>>>>>>>>>>>>>>>
>>>>>>>>>>>>>>>>
>>>>>>>>>>>>>>>>
>>>>>>>>>>>>>>>>
>>>>>>>>>>>>>>--
>>>>>>>>>>>>>>Evelyn Camon
>>>>>>>>>>>>>>GOA Coordinator
>>>>>>>>>>>>>>Senior Scientific Curator
>>>>>>>>>>>>>>European Bioinformatics Institute
>>>>>>>>>>>>>>Tel:01223-494465
>>>>>>>>>>>>>>Fax:01223-494468
>>>>>>>>>>>>>>E-mail: camon at ebi.ac.uk
>>>>>>>>>>>>>>URL: http://www.ebi.ac.uk/goa
>>>>>>>>>>>>>>
>>>>>>>>>>>>>>
>>>>>>>>>>>>>>
>>>>>>>>>>>>>>
>>>>>>>>>>>>>
>>>>>>>>>>>>>
>>>>>>>>>>>>>
>>>>>>>>>>>>>
>>>>>>>>>>>>-- Evelyn Camon
>>>>>>>>>>>>GOA Coordinator
>>>>>>>>>>>>Senior Scientific Curator
>>>>>>>>>>>>European Bioinformatics Institute
>>>>>>>>>>>>Tel:01223-494465
>>>>>>>>>>>>Fax:01223-494468
>>>>>>>>>>>>E-mail: camon at ebi.ac.uk
>>>>>>>>>>>>URL: http://www.ebi.ac.uk/goa
>>>>>>>>>>>>
>>>>>>>>>>>>
>>>>>>>>>>>>
>>>>>>>>>>>>
>>>>>>>>>>>>
>>>>>>>>>>>>
>>>>>>>>>>>
>>>>>>>>>>>
>>>>>>>>>>
>>>>>>
>>>>>>--
>>>>>>David P. Hill, Ph.D.
>>>>>>Senior Scientific Curator
>>>>>>Mouse Genome Informatics
>>>>>>Gene Ontology Consortium
>>>>>>The Jackson Laboratory
>>>>>>600 Main Street
>>>>>>Bar Harbor, ME 04609-1500
>>>>>>tel:207-288-6430
>>>>>>htpp://www.informatics.jax.org
>>>>>>http://www.geneontology.org
>>>>>
>>>>>
>>>>--
>>>>David P. Hill, Ph.D.
>>>>Senior Scientific Curator
>>>>Mouse Genome Informatics
>>>>Gene Ontology Consortium
>>>>The Jackson Laboratory
>>>>600 Main Street
>>>>Bar Harbor, ME 04609-1500
>>>>tel:207-288-6430
>>>>htpp://www.informatics.jax.org
>>>>http://www.geneontology.org
>>>
>>
>
>
>--
>Alexander Diehl, Ph.D.
>Scientific Curator
>Mouse Genome Informatics
>The Jackson Laboratory
>600 Main Street
>Bar Harbor, ME  04609
>
>email:  adiehl at informatics.jax.org
>work:  +1 (207) 288-6427
>fax:  +1 (207) 288-6131
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