Chaperones

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Intro

As part of the transporter activity overhaul it has become apparent that the chaperone terms need some work. We are planning to do this straight after the transporter activity implementation goes live.

Background

The most recent email thread (March 2007):

Val 26 Mar 2007 18:08:20

Summary, as I understand it: (CCing Midori too...Midori do you remember any lurking SF entries or action items relating to this?)

'metallochaperone' and 'protein folding chaperone' will be direct children of 'molecular function'

ONLY 'protein transport chaperone' will be a child of transporter activity

NONE would have any term or relationship under 'transmembrane transporter activity'

(Need to explain a bit about why this is necessary)

The only SF entry I can see is mine here [1233407] but I'm sure this has been discussed in other SF items and possibly even at annotation camp. Jen can you find any other background for this? it would give it more weight.....

If you two could comment, then Jen perhaps this could go to the transport interest group, Maria, Rama, and David for further comments?

This is my first attempt

I propose we resurrect this and the def (or something very similar)

chaperone activity

OBSOLETE. Assists in the correct non-covalent assembly of polypeptide-containing structures in vivo, but is not a component of these assembled structures when they are performing their normal biological function.
This term was made obsolete because, as defined, it represents a class of gene products rather than a molecular function. The term string is also ambiguous, having connotations of involvement in transport processes. To update annotations, consider the molecular function term 'unfolded protein binding ; GO:0051082' and the biological process term 'protein folding ; GO:0006457' and its children.

rename as
protein folding chaperone activity
synonym chaperone activity
Assists in the correct non-covalent assembly of polypeptide-containing structures in vivo, by binding unfolded proteins to stabilize and prevent aggregation. Chaperones do not form a part of the assembled structures when they are performing their normal biological function.

protein transport chaperone

A protein which recognises and binds a protein substrate and transports it within the cell via a protein trafficking mechanism.???

a child would be protein carrier activity and would have a def consistent with the eventual def for protein transport chaperone

a child of this would be
GO:0008262 : importin-alpha export receptor activity (gene product)
renamed to:
nucleocytoplasmic protein carrier activity
This would deal with SF [1455372]

metallochaperone activity

Assists in the delivery of metal ions to target proteins (need to extend this def)

Midori 26 Mar 2007 20:51:36

I can't think of anything else open on SF. There are some closed items that may provide background; search for 'chaperone'.

  1. I would definitely leave the old chaperone term (GO:0003754) obsolete, because it was used sloppily when it was 'live', as though it meant both protein folding chaperone and transport chaperone. A new 'protein folding chaperone activity' term should get a new ID; I might also massage the definition a little, e.g. 'interacting selectively with unfolded proteins, thereby assisting in the correct non-covalent assembly of polypeptide-containing structures in vivo, and preventing aggregation. Chaperones do not form part ...' Finally, could it go under protein binding?
  2. The definition of protein transport chaperone starts off with 'a protein which' ... that won't do as a definition of an activity (and if it's not an activity, it doesn't belong in the function ontology). Maybe 'interacting selectively with a protein substrate and transporting it within the cell'? Also not sure what a 'protein trafficking mechanism' is, so that bit might need a bit more explanation.

Val 27 Mar 2007 11:28:58

I would definitely leave the old chaperone term (GO:0003754) obsolete, because it was used sloppily when it was 'live', as though it meant both protein folding chaperone and transport chaperone. A new 'protein folding chaperone activity' term should get a new ID; I might also massage the definition a little, e.g. 'interacting selectively with unfolded proteins, thereby assisting in the correct non-covalent assembly of polypeptide-containing structures in vivo, and preventing aggregation. Chaperones do not form part ...' Finally, could it go under protein binding?

Yes to all

The definition of protein transport chaperone starts off with 'a protein which' ... that won't do as a definition of an activity (and if it's not an activity, it doesn't belong in the function ontology). Maybe 'interacting selectively with a protein substrate and transporting it within the cell'? Also not sure what a 'protein trafficking mechanism' is, so that bit might need a bit more explanation.

OK I know my defs were crap and you'd be able to sort them;)

I went digging about in my archive and the Protein trafficking suggestion is wrong for nucleocytoplasmic transport if we follow this wisdom from john Armstrong:

"'Protein targeting' means targeting individual proteins to specific organelles e.g. the ER, the mitochondria, the peroxisome, the nucleus. 'Protein traffic' means moving groups of proteins and lipids in vesicles between organelles."

So if nucleocytoplasmic transport comes under targeting--targeting is dependent on some intrinsic sequence in the protein. There is always some dependency on a signal sequence for nucleocytoplasmic transport (either within the protein or within a protein that the transported protein is attached to)

This agrees with this description from Shelly Sazer:

"There are two types of "classical" NLS whose sequences have been defined and have pretty reliable consensus sequences. These are the SV40 mono-partite NLS and the nucleoplasmin bi-partite types of NLS, and generally when people talk about NLSs they are referring to this type. These proteins are imported to the nucleus by a complex of importin alpha and importin beta. There are other proteins that do not have a classical NLS and bind directly to importin beta for import, but the consensus sequences for this has not been defined. Lastly, there are proteins that do not have any NLS but bind to another protein that contains an NLS which is responsible for transporting the protein into the nucleus. So, amongst this second class are proteins that do not have a "classical" NLS, but if we take the definition of NLS as a sequence that directs a protein to the nucleus, then these proteins do have an NLS."

so......How about

protein transport chaperone

'interacting selectively with a protein substrate and transporting it within the cell'

This mechanism is dependent on a protein targeting mechanism which requires a signal sequence within the transported protein or one of its binding partners ?

Although this would not work for some things which are currently annotated to protein carrier. Some COPII vesicle proteins which are annotated to this term (although I'm not sure that they should be?).....these work by a trafficking mechanism

Also, can we make it clear in the def somehow that this does not refer to targetting across a membrane (i.e ER translocation etc)

In fact, Jen, this is another term we need to consider at this point:

SNAP receptor activity is a child of intracellular transporter activity and has the very 'untransporty' def:

Acting as a marker to identify a membrane and interacting selectively with one or more SNAREs on another membrane to mediate membrane fusion.

perhaps

protein binding
--protein transport chaperone
----nucleocytoplasmic protein transport chaperone
--SNAP receptor activity
--protein folding chaperone

transporter activity
----protein transport chaperone
----nucleocytoplasmic protein transport chaperone

obsolete protein carrier (used in different contexts)

ther term name "protein transport chaperone" bothers me a bit. What we mean here is a 'chaperone type transporter' Is there a better 'term name?'

Any closer?

Jen 27 Mar 2007 11:35:30

Hi Val,

Here's all I can find. It makes good reading.

First some not very relevant SF items:

I also found this:

https://sourceforge.net/tracker/index.php?func=detail&aid=1170774&group_id=36855&atid=440764

which mostly says that nobody has time to think about chaperones.

There is this:

https://sourceforge.net/tracker/index.php?func=detail&aid=935116&group_id=36855&atid=440764

That really doesn't say anything.

Then the exciting stuff in approximately chronological order:

https://sourceforge.net/tracker/index.php?func=detail&aid=869662&group_id=36855&atid=440764

This is where the chaperone terms was obsoleted causing much harrassment.

Then there is an angry exchange on the GO list.
Subject line: GO:0003754 , chaperone activity 22/7/04

http://genetics.stanford.edu/go-email/email-go/go-arc/go-2004/1697.html

This is never really resolved and so it goes to the consortium meeting.

Then the semi-conclusive discussion in the Chicago meeting.

http://www.geneontology.org/GO.meetings.shtml#consort

I have pasted the whole discussion below. There isn't a concrete conclusion but the way is made for us to think creatively about how to deal with chaperones. I think this is particularly pertinent just now since we are now ramping up to connect the function and process ontologies.

4. Other Content Proposals for Discussion
a) removal of terms

This discussion centered on the tension between "ontological purity" and "scruffy necessity". Some members of the group feel that too many terms are obsoleted, too quickly; this creates a lot of re-curation work and may adversely affect the way users look at our project. The mandate of the GO editorial group is ontological purity, but perhaps this needs to be re-evaluated. If a widely used terms describing well-known gene products (e.g., cytochrome P450) disappear, that does not serve our user community. Everyone agreed that increased use of synonyms could help this situation. Term names can be made more precise, while commonly used, imprecise terms could be synonyms. Synonyms should be used liberally, and we should improve our use and display of them in various tools.

Some were concerned that "vague" terms that represent extremely important concepts for biologists (transcription factor activity, chaperone activity, G-protein coupled receptor) have been obsoleted or may be slated for obsoletion. The argument was made that these terms do have clear meanings for scientists, and they represent special cases that need to be preserved. Retaining them may even lead to blurring of the line between function and process, but we should permit this for these special cases. Chris proposed a less severe form of obsoletion, where a term is deprecated but not immediately removed. David suggested that if if all annotations to a term are automatically transferrable to its new equivalent, then the obsoletion should not have happened in the first place; the definition of the original term should have been improved, or the term should have been merged with another.

We discussed the specific case of ?chaperone activity?, which has been obsoleted. Rama explained that the word ?chaperone? is used to mean three separate activities: transporting something; unfolded protein binding; and unfolded protein binding and re-folding activity. David suggested creating a lexical grouping term to be the parent of all three of these activities. Amelia thought that this would not make sense and would be analogous to creating a term ?factor activity? to group all ?factors?. Judy suggested that we could include lexical grouping terms in the GO, but tag them in some way to mark them as "impure". However, some thought this solution was simplistic, and others thought there would be no point in tagging a term if people would go on using it as before. Amelia suggested that we could create special terms crossing the process/function line, e.g., transcription factor could be a child of process: transcription and function: DNA binding activity. Chris observed that tagging would address the problem of vague terms, while cross-parentage addresses the problem of precise, complex terms.

Summary: We need to use synonyms more aggressively and liberally. We can't achieve purity, so we need to explore options for alternative solutions when they become necessary. We need to write up examples for ways to deal with exceptional terms. There was no consensus on whether lexical grouping terms or cross-aspect terms are a good idea. The group recognizes that there are exceptions that need special attention rather than immediate obsoletion. The definition may need reworking, or we may need to implement special solutions.

As far as I can see the summary is that Amelia ony wants single step functions and thinks that chaperones are a class of gene product. Judy, Michael and Harold feel that chaperone is complex function and was a great loss to the function ontology that should never have occurred.

Val suggested the transport and folding chaperone terms but no one replied.

Does this seem a reasonably comprehensive list of the discussions?

There's another GO list thread about heat shock but I don't think it's relevant to our current discussion.

Having reviewed all this I'm very tempted to save taking it on until we have fixed and implemented all the transport stuff. It seems like the sort of discussion that would take a lot of time to think through and discuss properly. Also I wouldn't like to risk that the chaperone discussion might hold back or derail the transport work. What would you think about doing this as the very next step after we implement the transport improvements?

We could be thinking through what to do in the meantime but not actually float the idea until the safe and easy tranport work is accepted and committed.

Jen

Val 27 Mar 2007 11:56:35

After scanning the thread, I think that what we propose should make everyone reasonably happy.

I think it acknowledges Amelia's issue that these really are protein binding terms because they will be under protein binding. I agree with Amelia that they aren't really single functions, but I think this will make everybody reasonably happy and make it easier for curators to annotate and for biologist to find the right thing until the happy day when the process and function ontologies are seamlessly merged into one ;)

Jen, I agree that we shouldn't discuss this until we have got the major overhaul complete, but if we think along these lines (which is I think what the general consensus has moved towards at previous meetings), then we should spot any further problems with this implementation before we announce it.

We now have working defs and terms names which we can improve on.

Val


2nd October

Ruth Lovering and Val Wood have mentioned that they would be interested to get this chaperone work finished and implemented. Val is busy moving institute for the next month or so, but I will contact both of them in the middle of November to see if that would be a good time to start. (Jennifer)