chaperone/aggregation inhibitor

[gocentral]

Hi

This is an attempt to provide a name for chaperones that is not ‘chaperone’

NTR protein (or polypeptide) aggregation inhibitor activity: Interacting selectively with aggregation-prone protein folding intermediates, blocking the self-association reactions that lead to aggregate formation, without forming part of the final native protein structure. synonym: exact _ passive chaperone is_a child of GO:0051082 unfolded protein binding

NTR ATP-dependent protein (or polypeptide) aggregation inhibitor activity: Actively facilitating native protein folding by using the energy of ATP hydrolysis to alter the conformations accessible to a non-native protein, without forming part of their final native structure. May also inhibit formation of expanded and otherwise misfolded conformational states that slow or block folding of the protein in free solution. synonym: exact active chaperone narrow HSP70 family narrow multimeric GroEL chaperonin narrow chaperonins is_child of NTR protein aggregation inhibitor activity

NTR protein (or polypeptide) disaggregation activity re-solubilizes or unfolds polypeptide aggregates synonym: narrow ClpB narrow Hsp104 is_a child of GO:0051082 unfolded protein binding

NTR: Protein aggregation inhibitor activator activity Increases the activity of protein aggregation inhibitor. synonym: narrow _ co-chaperone narrow _chaperone cofactor narrow _chaperone activator is_a child of GO:0051087 chaperone binding

Example proteins in each class:

1. Protein aggregation inhibitor activity a. SecB, which is an ATP-independent chaperone b. Prefoldin (prefoldin that is used in the formation of actin or tubulin,eg transfers β tubulin or α tubulin to a cytosolic chaperonin), does not necessarily lead to folding of protein, but definition covers this. c. nascent-polypeptide-associated complex (NAC) in S. cerevisiae and mammals, 2004 review wasn’t sure that NAC was chaperone, but if it is may act through the simple binding and protection of hydrophobic peptide stretches. d. Trigger factor (TF, Tig P0A850 E.coli)

2. ATP-dependent protein aggregation inhibitor activity a. heat-shock protein (Hsp70) family (eg DnaK) b. the ribosome-associated complex (RAC) in Saccharomyces cerevisiae c. chaperonin GroEL d. eukaryotic chaperonin TCP1 ring complex (TRiC) e. HSP90 f. HSC70/ HSPA8 g. chaperonin CCT h. Hsp70 proteins (Ssb1 and Ssb2

3. Protein disaggregation activity a. re-solubilization of polypeptide aggregates by the AAA PROTEINS ClpB in E. coli and Hsp104 in S. cerevisiae.

4. Protein aggregation inhibitor activator activity a. Co-chaperone –GroES, positively regulates activity of GroEL and enables release of bound protein b. mammalian co-chaperone Hsp-organizing protein (HOP; which is known as Sti1 in Saccharomyces cerevisiae) c. mammalian co-chaperone TPR2 (which is also known as TTC2 or DJC7) d. DNAJ/HSP40 family, regulate molecular chaperone activity by stimulating ATPase activity. Also substrate polypeptides that are transiently bound by the cofactor protein DnaJ are transferred onto DnaK e. HSP90 cofactor p23 f. Zuotin g. Activator of HSP90 ATPase (AHA1) h. CDC37 i. HSP40/HDJ1, HDJ2

Note I have not included a term to describe ‘Unfolded-protein peptidyl-prolyl cis-trans isomerase activity’. Although trigger factor (TF, Tig P0A850 E.coli) has this activity the significance of the peptidyl-prolyl cis–trans isomerase activity of TF remains unclear, as the prolyl isomerase domain is not essential for the chaperone function of TF. TF is thought to function by scanning a nascent chain as it is extruded from the exit site and shielding hydrophobic stretches to keep them soluble, therefore just included this as an example under aggregation inhibitor.

I am not sure how to describe proteins that regulate the activity of the ‘chaperones’ listed above. However, whilst I appreciate that these are a heterogeneous group, GO has terms such as GO:0030547 receptor inhibitor activity, which must also cover quite a large range of protein functions. Therefore I am reluctant to give up on them yet, although I appreciate that having protein specific terms is not appropriate. I could only find examples of proteins that increase the chaperone activity or act as co-chaperones.

Ruth

Reported by: RLovering

Original Ticket: "geneontology/ontology-requests/5793":https://sourceforge.net/p/geneontology/ontology-requests/5793

[gocentral]

Hi Ruth,

I think that 'protein aggregation inhibitor activator activity' is a good descriptive term, although I remain unconvinced as to why the term 'protein (or polypeptide) chaperone' cannot be used. I have always thought of 'protein chaperone' as a function of a protein.

Varsha

Original comment by: vkhodiyar

[gocentral]

• assigned_to: nobody --> tairtb

Original comment by: mah11

[gocentral]

Hi Is there a problem with the suggestion I have made? Thanks Ruth

Original comment by: RLovering

[gocentral]

We would like to hear feedback from Rama, Amelia, and David. I will email them separately to follow up. (Amelia and David are currently still out.)

Some thoughts:

For the the first term requested, 'protein (or polypeptide) aggregation inhibitor activity', how about 'negative regulation of identical protein binding' instead?

This new term could be an is_a child of 'negative regulation of protein binding; GO:existing' AND a negatively_regulates child of the FUNCTION 'identical protein binding; GO:existing'. This approach utilizes the new ability to make inter-ontology links and the existing ontology structure quite nicely.

so:

molecular function --[i]binding ----[i]protein binding ------[i]identical protein binding --------[neg reg]negative regulation of identical protein binding (NEW)

biologial process --[i]regulation of molecular function ----[i]regulation of binding ------[i]negative regulation of binding --------[i]negative regulation of protein binding ----------[i]negative regulation of identical protein binding (NEW) ------[i]regulation of protein binding --------[i]negative regulation of protein binding ----------[i]negative regulation of identical protein binding (NEW)

I certainly DO want to be able to annotate chaperone proteins correctly. Since there has been so much discussion on this topic over the years, I would like to make sure that the terms that we create to do so are both defined and placed correctly in the graphs.

More input welcome.

Original comment by: tberardini

[gocentral]

Hi,

I will take a look and comment soon.

Rama

Original comment by: rbalakri

[gocentral]

Hi,

Sorry it took me so long. Here are my comments. I am very open to discussion on this.

1) Protein aggregation inhibitor activity:

I agree with Tanya. This should be covered by Process terms. negative regulation of identical protein binding works. There is also a term called 'regulation of protein stability' and from its definition, i think it can be used for this case. We can make positive and negative regulation child-terms under it.

2) ATP-dependent protein (or polypeptide) aggregation inhibitor activity: This is nothing but the entire protein folding or refolding process. I wouldn't make a MF term for this. And we don't want to have a term called ATP_dependent protein folding (see: SF item on ATP dependent proteolysis #- 2635152- https://sourceforge.net/tracker/index.php?func=detail&aid=2635152&group\_id=36855&atid=440764) we can make ATP dependent blah as a synonym like in the proteolysis case.

3) protein disaggregation activity- is the same process of protein stabilization? already covered by BP term GO: 50821

4) Protein aggregation inhibitor activator activity (tongue/mind twister)- i think the gp of interest here activates the ATPase activity of the chaperone. This should be annotated using the BP term (or its children) "regulation of ATPase activity"

Thanks,

Rama

Original comment by: rbalakri

[gocentral]

All these terms sound like processes that have been converted into function terms, not actual functions. I think the actual functions that chaperones perform are probably binding and catalytic activities like isomerization. Maybe it's time for a 'class' ontology so annotators can keep the info that a gene product is described as a chaperone?

Original comment by: girlwithglasses

[gocentral]

The protein ontology (PRO) would be just the place for chaperones, methinks.

m

Original comment by: mah11

[gocentral]

Hi

sorry I have several points on this:

1. I like the idea of protein ontology (PRO) but how would this be used by GO exactly?

2. undoubtedly chaperones bind proteins so I guess this function is an agreed function.

3. I would be very disappointed if the only way to describe the function 'chaperone activity' is by using a process term 'negative regulation of identical protein binding, and also 'positive regulation of protein folding' However a chaperone on it own has the ability to facilitate the folding of proteins which prevents aggregation.

NOTE that the regulation terms for function terms will not be included in the majority of tools using or displaying GO and therefore annotations to these terms will not be used in, for example, microarray analysis. Furthermore it is not possible to include these regulation of function terms in GO slims as a chaperone clearly does not have the function 'identical protein biding' so even if these terms do make it into a few tools these annotations would be deleted in GO slims.

4. Looking at the definition for isomerization I am not convinced that chaperones catalyze isomerization.

5. I can see that folding of proteins could be viewed as a process, however I believe that folding of proteins is a single functional activity, wikipedia decription of chaperonins http://en.wikipedia.org/wiki/Chaperonin:

Chaperonins undergo large conformational changes during a folding reaction as a function of the enzymatic hydrolysis of ATP as well as binding of substrate proteins and cochaperonins, such as GroES. These conformational changes allow the chaperonin to bind an unfolded or misfolded protein, encapsulate that protein within one of the cavities formed by the two rings, and release the protein back into solution. Upon release, the substrate protein will either be folded or will require further rounds of folding, in which case it can again be bound by a chaperonin.

The process would be the rebinding again and again until correct folding was achieved if necessary.

Note that when a transmembrane receptor binds a ligand and perhaps this leads to autophosphorylation to enable the transmission of the signal from ligand binding to an internal signal transduction pathway. Very few transmembrane receptor are made up of a single protein, or homodimer, and many are heterodimers which only bind ligands as a dimer. I would suggest that you could consider transmembrane receptor activity as a process with 2 activities: ligand binding, kinase activity and yet we have the function GO term transmembrane receptor activity with an extensive ontology associated with it.

Note that in the case of ATP dependent proteolysis we chose the function term ATP dependent peptidase over the process term.

6. I agree the terms I have suggested are very cumbersome and that actually it would be far better to use the correct scientific term: chaperone, just as we use the term: receptor, rather than trying to describe this using process style language.

7. revised suggestion: GO:0005515 protein binding > protein folding chaperone activity >> ATP-dependent protein folding chaperone activity

GO:0051087 chaperone binding > protein folding chaperone binding >> protein folding co-chaperone activity > metallochaperone binding

NTR protein folding chaperone activity: Interacting selectively with aggregation-prone protein folding intermediates, blocking the self-association reactions that lead to aggregate formation, without forming part of the final native protein structure. synonym: exact _ passive chaperone is_a child of GO:0005515 protein binding Note I have NOT put this as a child term of either GO:0051082 unfolded protein binding or GO:0051787 misfolded protein binding because I am not sure that all chaperones bind misfolded and unfolded proteins.

NTR ATP-dependent protein folding chaperone activity: Actively facilitating native protein folding by using the energy of ATP hydrolysis to alter the conformations accessible to a non-native protein, without forming part of their final native structure. May also inhibit formation of expanded and otherwise misfolded conformational states that slow or block folding of the protein in free solution. synonym: exact active chaperone narrow HSP70 family narrow multimeric GroEL chaperonin narrow chaperonins narrow ClpB narrow Hsp104 is_child of NTR protein folding chaperone activity

NTR: protein folding chaperone binding Interacting selectively with a chaperone protein, a class of proteins that bind to nascent or unfolded polypeptides and ensure correct folding. is_a child of GO:0051087 chaperone binding

NTR: metallochaperone binding Interacting selectively with a chaperone protein, a class of proteins that bind to nascent or unfolded polypeptides and ensure correct transport. is_a child of GO:0051087 chaperone binding

NTR: protein folding co-chaperone activity Increases the activity of protein folding chaperone protein, a class of proteins that bind to nascent or unfolded polypeptides and ensure correct folding. synonym: narrow _ co-chaperone narrow _chaperone cofactor narrow _chaperone activator is_a child of NTR protein folding chaperone binding

Ruth

Original comment by: RLovering

[gocentral]

Added this comment from Jim, which he had added to the SF item: [ 2526210 ] MF regulator terms for obsoletion

Date: 2009-01-26 21:12 Sender: jimhu Perhaps I'm not getting what a "narrow synonym" is, but my reaction is similar to Ruth's. For the GroEL/Cpn60 family of protein folding chaperones, and also for the Clp chaperones, unfolded protein binding is part of what they do, but not all of what they do. For GroEL, there is ATP-independent and ATP-dependent activity. The latter is required for some classical substrates, such as Rubisco, while improved folding happens for others with "just" protein binding and release.

It also isn't clear to me that what they do is strictly catalysis. Catalysis increases the rate at which a equilibrium is reached. Folding of chaperone substrates isn't really an equilibrium process - the equilibrium state is scrambled egg aggregated precipitates. There are active arguments about mechanism, but it seems clear that at least part of what chaperones do is to allow proteins that have gone down a nonproductive pathway to take another shot at the native state. There's evidence for GroEL that the process is more than that - there seems to be active pulling apart of the partially misfolded state.

We just had a seminar here about this recently; see PMID: 18311152

Original comment by: RLovering

[gocentral]

Added to Eugene GO meeting agenda. We'll make sure to schedule this at a time that the UK folks will be able to attend. Likely on Tuesday morning, Pacific time.

Original comment by: tberardini

[gocentral]

GO clinic September 2009 NTR created: GO:0044183 protein binding involved in protein folding which addresses this SF item

Original comment by: RLovering

[gocentral]

• status: open --> closed

Original comment by: RLovering