Protein Ontology:

Addressing the need for precision in representing protein networks

Darren A. Natale, Ph.D.Protein Science Team Lead, PIRResearch Assistant Professor, GUMC

Workshop on Ontologies of Cellular NetworksMarch 2008

IEV_0000090

part_of

IEV_0000156

IEV_0000159

IEV_0000155

IEV_0000157

IEV_0000158

4 Binding of R-smad:smad4 complex and responsive element

2 Complex formation of R-smad and Smad4

5 Transcription by R-smad:smad4

1 Phosphorylation of R-smad by TGF beta receptor I

3 Nuclear import of R-smad:smad4

TGF- signaling pathwayExample from: INOH Event Ontology

R-smad

R-smad

R-smad:

R-smad:

R-smad:

Smad4

smad4

smad4

smad4

TGF beta receptor I

responsive element

Actions Locations

Nucleus

Cytoplasm

nuclear membrane

Roles

IMR_0000369Txn regulator

IMR_0000370SMAD

IMR_0000372Co-Smad

IMR_0000371R-Smad

IMR_0000373I-Smad

IMR_0100312Smad3

IMR_0100311Smad2

IMR_0100313Smad5

IMR_0100310Smad1

IMR_0100314Smad8

is_a

Example from: INOH Molecule Role Ontology

IMR_0100315Smad4

The Roles Played

IMR_0704004SMAD2_HUMAN

sequence_of

Cellular Component:- nucleus

Molecular Function:- protein binding

Biological Process:- signal transduction- regulation of transcription, DNA-dependent

Mothers against decapentaplegic homolog 2

Smad 2

GO annotation of SMAD2_HUMAN:

II I

TGF-TGF-beta receptor

PP Smad 4

4 DNA binding

1 phosphorylation

2 complex formation

Nucleus

Cytoplasm

Smad 2

Smad 2

PPSmad 2

Smad 4

5 Transcription Regulation

PPSmad 2

Smad 4

3 nuclear translocation

PPSmad 2PP

P

++

ERK1CAMK2

PP

“normal” •Cytoplasmic PRO:00000011 REACT_7257.1

TGF- receptor phosphorylated

•Forms complex•Nuclear•Txn upregulation

PRO:00000013REACT_7563.1

ERK1 phosphorylated •Forms complex•Nuclear•Txn upregulation++

PRO:00000014

CAMK2 phosphorylated

•Forms complex•Cytoplasmic•No Txn upregulation

PRO:00000015

alternatively spliced short form

•Cytoplasmic

PRO:00000016REACT_7906.1

phosphorylated short form

•Nuclear•Txn upregulation PRO:00000018

REACT_7100.1

point mutation (causative agent: large intestine carcinoma)

•Doesn’t form complex•Cytoplasmic•No Txn upregulation

PRO:00000019

Smad 2

PPSmad 2

PPSmad 2P

PPSmad 2 P

Smad 2 x

Smad 2

Smad 2 PP

SMAD2_HUMAN

SMAD2_HUMAN

SMAD2_HUMAN

SMAD2_HUMAN

SMAD2_HUMAN

SMAD2_HUMAN

SMAD2_HUMAN

%PRO:00000010 Smad2 %PRO:00000011 Smad2 isoform 1 (long form) %PRO:00000012 Smad2 isoform 1 phosphorylated form %PRO:00000013 Smad2 isoform 1, TGF- receptor I-phosphorylated %PRO:00000014 Smad2 isoform 1, TGF- receptor I and ERK1-phosphorylated

arises_from SO: amino_acid_substitutionNOT has_modification MOD: phosphorylated residueNOT has_function GO: transcription coactivator activitygives_rise_to DO: carcinoma of the large intestine

%PRO:00000015 Smad2 sequence 1, TGF- receptor I and CAMK2-phosphorylated %PRO:00000016 Smad2 sequence 2 (short form) - splice variant %PRO:00000017 Smad2 sequence 2 phosphorylated form %PRO:00000018 Smad2 sequence 2, TGF- receptor I-phosphorylated %PRO:00000019 Smad2 sequence 3 - genetic variant related to colorectal carcinoma

%PRO:00000015 Smad2 isoform 1, TGF- receptor I and CAMK2-phosphorylated %PRO:00000016 Smad2 isoform 2 (short form) - splice variant %PRO:00000017 Smad2 isoform 2 phosphorylated form %PRO:00000018 Smad2 isoform 2, TGF- receptor I-phosphorylated %PRO:00000019 Smad2 isoform 3 - genetic variant related to colorectal carcinoma

has_modification MOD:O-phosphorylated L-serinehas_modification MOD:O-phosphorylated L-threoninehas_function GO: TGF- receptor, pathway-specific cytoplasmic mediator activityhas_function GO:SMAD bindinghas_function GO:transcription coactivator activity participates_in GO:signal transduction participates_in GO:SMAD protein heteromerization participates_in GO:regulation of transcription, DNA-dependent located_in GO:nucleus part_of GO:transcription factor complex

ProEvo

ProForm

GO Gene Ontology

molecular function

cellular component

biological process

participates_in

part_of (for complexes) located_in (for compartments)

has_function

PRO http://pir.georgetown.edu/proprotein

Root Levelis_a

translation product of an evolutionarily-related gene

translation product of a specific mRNA

Family-Level Distinction• In common: specific ancestor• Source: PIRSF family

Modification-Level Distinction• In common: specific translation product• Source: UniProtKB

Sequence-Level Distinction• In common: specific allele or splice variant• Source: UniProtKB

cleaved/modified translation product disease

DO/UMLS Disease

agent_of

is_a

protein modification

has_modification

PSI-MOD Modification

SO Sequence Ontology

sequence change

arises_from (sequence change) gives_rise_to (effect on function)

is_a

protein domain

has_part

Pfam Domain

Example:

TGF- receptor phosphorylated smad2 isoform1

is a phosphorylated smad2 isoform1

is a smad2 isoform 1

is a smad2

is a TGF- receptor-regulated smad

is a smad

is a protein

Modification Level

Sequence Level

Family Level

Root Level

translation product of a specific geneGene-Level Distinction• In common: specific gene• Sources: PIRSF subfamily, Panther subfamily

is_a

Gene Level

IEV_0000090

part_of

IEV_0000156

IEV_0000159

IEV_0000155

IEV_0000157

IEV_0000158

4 Binding of R-smad:smad4 complex and responsive element

2 Complex formation of R-smad and Smad4

5 Transcription by R-smad:smad4

1 Phosphorylation of R-smad by TGF beta receptor I

3 Nuclear import of R-smad:smad4

TGF- signaling pathwayExample from: INOH Event Ontology

R-smad

R-smad

R-smad:

R-smad:

R-smad:

Smad4

smad4

smad4

smad4

TGF beta receptor I

responsive element

Actions Locations

Nucleusnuclear membrane

Roles

Actors

smad2

smad2

smad2:

smad2:

smad2:

P P

P P

P P

P P

P P

has_participant PRO:smad4has_participant PRO:TGF- receptor-phosphorylated smad2

P

P

P

P

P

Transcription

has_participant PRO:smad4has_participant PRO:TGF- receptor & ERK1-phosphorylated smad2

Cytoplasm

PRO Team (so far…)•Principle Investigators

Cathy Wu (PIR at GUMC)Judith Blake (The Jackson Laboratory)Barry Smith (SUNY Buffalo)

•Curators & DevelopersCecilia Arighi (PIR at GUMC)Winona Barker (PIR at GUMC)Harold Drabkin (The Jackson Laboratory)Zhang-zhi Hu (PIR at GUMC)Hongfang Liu (GUMC)Darren Natale (PIR at GUMC)

Official Launch:March 31, 2008

http://pir.georgetown.edu/pro