User Community Interactions - Impact on PRO - Darren A. Natale, Ph.D. Protein Science Associate Team Lead, PIR Research Assistant Professor, GUMC Protein Ontology 3 rd Annual Meeting (2010)

PRO Users (Current & Potential) - a few examples - Ontology Providers Dendritic Cell Ontology (DC_CL) Semantic Resources Royal Society of Chemistry (RSC) Science Collaboration Framework Semantic Web Applications in Neuromedicine (SWAN) Process-Modeling Resources Reactome, MouseCyc EcoCyc Pathway Logic Molecule-Modeling Resources Database of Protein Disorder (DisProt) Int’l Union of Basic and Clinical Pharmacology (IUPhar)

Ontology Providers - Dendritic Cell Ontology - Describes different types of cells, sometimes using surface-expressed proteins to distinguish them [Term] id: DC_CL: name: conventional dendritic cell def: "conventional dendritic cell is_a leukocyte that has_high_plasma_membrane_amount_relative_to_leukocyte CD11c and lacks_plasma_membrane_part CD19, CD3, C34, and CD56." [AMM:amm] comment: Immunological Reviews : intersection_of: CL: ! leukocyte intersection_of: has_high_plasma_membrane_amount_relative_to_leukocyte PRO: ! CD11c intersection_of: lacks_plasma_membrane_part PRO: ! CD19 intersection_of: lacks_plasma_membrane_part PRO: ! CD34 intersection_of: lacks_plasma_membrane_part PRO: ! CD56 intersection_of: lacks_plasma_membrane_part PRO: ! CD3

PRO Content - before - Focused on mouse and human proteins Strictly species-neutral Small-scale Strictly single-molecule Protein forms were highly specific No derivation information

Seeks to tag chemistry articles with links to further information about the tagged entities, including proteins. Example:p21ras, heregulin (plus many others that PRO lacked). Highlighted the need for a large-scale expansion of terms. Semantic Resources - Royal Society of Chemistry -

PRO Content - after - Focused on mouse and human proteins Strictly species-neutral Small-scale Strictly single-molecule Protein forms were highly specific No derivation information

Semantic Resources - Science Collaboration Framework - Contains linkouts to model organisms, genes, cell lines, and – most pertinent to PRO – antibodies against proteins Example: antibodies against HSP70 proteins, which might be cross-reactive against several species, but might also react only against HSP70 from a single species. Highlighted the need to add species-specific terms to PRO. This required the addition of NCBI taxon terms.

PRO Content - after - Focused on mouse and human proteins Strictly species-neutral Small-scale Strictly single-molecule Protein forms were highly specific No derivation information

Models the proteins involved in the etiology of Alzheimer disease, and in particular the proteolytic cleavage products of amyloid beta A4 protein. Example: amyloid beta A4 protein is cleaved into a number of pieces, but not all isoforms can give rise to all pieces. Highlighted the need for the ability to indicate precursors for certain proteolytic cleavage products. Semantic Resources - AlzSWAN -

PRO Content - after - Focused on mouse and human proteins Strictly species-neutral Small-scale Strictly single-molecule Protein forms were highly specific No derivation information

Components may be protein complexes whose functions depend on modification state, or could have different components depending on the species Example: CDK2/cyclin A is activated by phosphorylation of T 160 while T 14 phosphorylation inactivates the kinase. Example: Mediator complex in humans has 36 subunits while yeast has 21. Highlighted the need for specific complexes with respect to both species and modification state. Process Resources - Reactome, MouseCyc -

PRO Content - after - Focused on mouse and human proteins Strictly species-neutral Small-scale Strictly single-molecule Protein forms were highly specific No derivation information

A rich source of protein forms and pathway information, similar to MouseCyc, except focused on Escherichia coli Example: NarQ Nitrate/Nitrite-Dependent Two-Component Regulatory System (not present in eukaryotes). Reaction: ATP+NarQ -> ADP+NarQ phosphohistidine Highlighted the need for bacterial protein representation. Process Resources - EcoCyc -

PRO Content - after - Focused on mouse and human proteins Strictly species-neutral Small-scale Strictly single-molecule Protein forms were highly specific No derivation information

Contains pathway descriptions whose components were known to be the product of a certain gene and known to be modified, but the position of the modification and the splice form were not known or were not important Example: phosphorylated BMX protein in EGF-mediated signaling pathway. Highlighted the need for general modified forms along the lines of protein -> phosphorylated protein. Process Resources - Pathway Logic -

PRO Content - after - Focused on mouse and human proteins Strictly species-neutral Small-scale Strictly single-molecule Protein forms were highly specific No derivation information

NCBI taxon OBI GO ChEBI SO MOD (conversion to ChEBI is under review) BFO

Relationship between UniProt & PRO All protein products from a particular gene (species-specific) Precise protein form (species-specific) – isoform 1 of human Smad2 phosphorylated on serine 144 Precise protein form (species-neutral) – isoform 1 of Smad2 from any species phosphorylated on the serine analogous to serine144 of human Smad2 isoform 1 All protein products from a particular gene (species-neutral) Not found anywhere yet as independent entry; though PRO will contain them; sometimes described in UniProtKB within a larger entry Currently covered by PRO “Whenever possible, all the protein products encoded by one gene in a given species are described in a single UniProtKB/Swiss-Prot entry” Currently covered by UniProtKB; Will need to be included in or referred to by PRO How to do it? Currently covered by PRO