Binding terms working group

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Working group

  • Ben Hitz
  • David Hill
  • Debbie Siegele
  • Emily Dimmer
  • Jim Hu
  • Mike Cherry
  • Peter D'Eustachio
  • Ruth Lovering

Summary

From the GO function guidelines (listed below) catalytic and transporter activities should not be related to binding terms.


The proposal is to remove substrate binding terms from GO whenever possible and ensure statements within the GO term directing GO curators to annotate to binding terms are removed where appropriate.

Examples:

1. Obsolete GO:0043287: poly(3-hydroxyalkanoate) binding

2. The term: GO:0016887 ATPase activity should NOT include the comment: Consider also annotating to the molecular function term 'ATP binding, GO:0005524'.

Please could comments on this be made by the end of Friday 8 May? (or suggest another date)

Pros

What these "binding" proposals all have in common is that they essentially want to track, for all enzymes the strict biochemical mechanism and all cofactors for each reaction, as well as all "relevant" substrate-product combinations. That is better left to some other database.

GO does not track biochemical reactions. It doesn’t track the reactants nor the products.

Should GO track protein kinase substrates? Glycolization sites? Ubiqutinylation substrates? GO needs to be consistent, why should GO partially track some reactants some of the time. That's not going to help anyone in the long run. In 99% of all cases, it will be better to cross index a database that is actually DESIGNED to store this sort of data.

This proposal suggests that we should remove from GO terms such as GO:0043287: poly(3-hydroxyalkanoate) binding and replace it with nothing - because this description of substrate binding is not the role of GO, and delete the majority of ATP binding annotations, ATP binding to only be associated with proteins which bind ATP as a co-factor.

Cons

Currently there are substantial numbers of binding terms associated with protein records by electronic means, for instance: 1,539,419 electronic annotations to just the ATP binding terms (versus 880 manual annotations), which include both 'substrate binding' and 'cofactor binding'. Furthermore, many of these terms are associated in a 'systematic manner', through for example protein domains, eg InterPro includes a number of domains which define a nucleotide binding site, for instance; IPR011761 ATP-grasp fold.

Do we need to remove substrate ATP binding annotations? It is useful for proteins to be grouped by the energy source they use to carry out a catalysis. For example the main purpose of an ATP-dependent enzyme, for instance a peptidase, is not to break down ATP, but to break peptide bonds.

It is going to involve a vast amount of work for the annotation groups to split up the nucleotide binding annotations into 'substrate binding' or 'cofactor binding' types.

In addition a large amount of information will be deleted from GO.

In order to preserve some of this information, but in a more appropriate ‘GO’ format could the GO terms provide an indication in the definition (or term's parentage) the specific ribonucleotide being used, e.g. making the term more specific 'GTP-dependent helicase activity', 'protein kinase activity' or expanding the ontology: >‘ribonucleotide-dependent catalytic activity’ >> ‘ATP-dependent catalytic activity’ This would follow previous terms such as: GO:0016723 'oxidoreductase activity, oxidizing metal ions, NAD or NADP as acceptor', as well as many specific terms e.g. 'GTP-dependent polynucleotide kinase activity', 'thymidylate synthase (FAD) activity', 'DNA ligase (ATP) activity', 'N-methylhydantoinase (ATP-hydrolyzing) activity').

This would at least mean that if any users had become accustomed to using the ATP binding annotation set to find those gene products that metabolised ATP, they could in future still gather together relevant gene products by using such a grouping term (and as a side benefit it could be helpful for curation consistency, if we could search for proteins co-annotated to 'ATP binding' and 'catalytic activity (ATP-hydrolysing)' then we would have reason to investigate further the validity of the 'ATP binding' annotation).

What would you like to see included or not included in the proposal for it to be acceptable?

  • Ben Hitz
  • David Hill
  • Debbie Siegele
  • Emily Dimmer
  • Jim Hu
  • Mike Cherry
  • Peter D'Eustachio
  • Ruth Lovering - I like the idea of having additional parent terms for the enzyme GO terms which enable a more specific description about the activity of the enzyme/transporter, eg: ‘ribonucleotide-dependent catalytic activity’ or 'ATP-hydrolyzing' but which do not include the word 'binding'.


Other aspects of the discussion to consider

Use of experimentally verified binding to support catalytic activity annotation

Ben to write comments in here.

Emily suggested: The paper, PMID: 10980193, partially characterizes a GTPase. It states that the protein is thought to be a GTPase, however this paper only measured its capacity to bind GTP, but not its GTPase activity directly. If this paper provided the only evidence for a possible GTPase activity, I would have considered annotating to the 'GTP binding' term, using the IDA evidence code, and referred to this annotation as providing supporting evidence for GTPase activity ('IC'). However, if we can no long annotate to GTP binding to proteins which use it as substrates, and assuming that this is the only evidence the curator can find to support an annotation to GTPase activity, how do curators feel about the alternative annotation to:

GTPase activity (GO:0003924) evidence='IPI' PMID:10980193 with='CHEBI:15422'

Data interpretation and other databases

Is there a single (or multiple) database which provides a source of this interaction information? If so, is it being used as a dataset for microarray analysis tools? If not why not? If GO removes binding interaction data what impact will it make on the interpretation of experimental datasets?

Other issues brought up in this discussion

This discussion also led to broader comments about the role of GO: Kinase substrate information should be stored in protein kinase substrate databases. Receptor binding should just be thrown out altogether as a term, except for actual LIGANDS. G-protein / GPCR interactions should be stored in a signalling pathway/protein-protein interaction databases.

From the Documentation for the Function Ontology

Binding guidelines

Avoid Binding Relationships

Catalytic activities should not be related to binding terms (see the September 2003 Bar Harbor GO meeting minutes); for example, ATPase activity should not be related to ATP binding. Similarly, there should not be a relationship between transporter terms and binding terms. Binding terms should only be used in cases where a stable binding interaction occurs. There are several reasons for this.

Firstly, transporter, catalysis and binding activities are all in the function ontology, which is used to describe elemental single step activities that occur at the macromolecular level. That means that if we were to further subdivide these functions - for example, splitting the catalysis of a reaction into steps such as "substrate binding", "formation of unstable intermediate" or "attraction of electrons to positive charge" - we would be saying that a reaction was actually a series of functions - i.e. a process. Additionally, we would be going beyond the scope of the molecular function ontology as we would be dealing with events on a molecular or atomic level.

Another reason is the sheer practicality of sorting through the 4000+ catalytic reactions we have in GO and deciding which of the substrates and products should be given 'binding' terms. Should we say that only substrates are bound by an enzyme? How about reversible reactions or cases where the reaction mechanism is unknown?

Finally, the GO binding terms are supposed to represent stable binding interactions, as opposed to the transient binding that occurs prior to catalysis. Hence there should not be a connection between stable binding and catalysis.

From the minutes of Bar Harbor GO Consortium Meeting 2003

BarHarbor minutes

Section 5) Ontology Development Issues

d) Consistency of Parentage (catalysis and binding) It was agreed that enzyme activities should have only the catalysis parent All binding parents to enzyme activities should be removed where appropriate.


Ontology Development Action Items 17. Document the fact that binding is not always a parent of enzyme. Binding is only a parent when stable binding occurs. Remove Binding as parent where appropriate.