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
