O75044 (SRGP2_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
SLIT-ROBO Rho GTPase-activating protein 2
Short name=srGAP2

Alternative name(s):
Formin-binding protein 2
Rho GTPase-activating protein 34

Gene names

Name:	SRGAP2
Synonyms:	ARHGAP34, FNBP2, KIAA0456, SRGAP2A

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	1071 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	RAC1 GTPase activating protein (GAP) that binds and deforms membranes, and regulates actin dynamics to regulate cell migration and differentiation. Plays an important role in different aspects of neuronal morphogenesis and migration mainly during development of the cerebral cortex. This includes the biogenesis of neurites, where it is required for both axons and dendrites outgrowth, and the maturation of the dendritic spines. Also stimulates the branching of the leading process and negatively regulates neuron radial migration in the cerebral cortex. Its interaction and inhibition by SRGAP2C reduces the rate of spine maturation, alters dendritic spine morphology and density and indirectly increases neuronal migration. It may have implications for cognition, learning and memory. In non-neuronal cells, it may also play a role in cell migration by regulating the formation of lamellipodia and filopodia. Ref.6 Ref.10 Ref.12
Subunit structure	Homodimer Probable. Forms a heterooligomer with SRGAP1 and SRGAP3 through its F-BAR domain. Interacts (via SH3 domain) with GPHN By similarity. Interacts with SRGAP2C; formation of the heterodimer alters SRGAP2 function. Interacts (via SH3 domain) with FMNL1 (activated by RAC1); regulates the actin filament severing activity of FMNL1 and actin dynamics. Interacts (via SH3 domain) with FMNL3. Interacts with RAC1; specifically stimulates RAC1 GTPase activity. Probably interacts with ROBO1 and ROBO2. Interacts with FASLG. Interacts with PRMT5. Ref.2 Ref.5 Ref.6 Ref.10 Ref.12 Ref.13
Subcellular location	Cell membrane. Cell projection › dendritic spine. Cell junction › synapse › postsynaptic cell membrane › postsynaptic density By similarity. Cell junction › synapse › postsynaptic cell membrane By similarity. Cell projection › lamellipodium. Cytoplasmic vesicle › phagosome By similarity. Nucleus By similarity. Cytoplasm By similarity. Note: Recruited to actin-rich phagosomes during phagocytosis By similarity. Translocates from nucleus to cytoplasm during development By similarity. Ref.6 Ref.10 Ref.12
Domain	The F-BAR domain mediates oligomerization, binds membranes, and induces plasma membrane protrusions. Ref.13
Post-translational modification	Methylation at Arg-927 is required for the stimulation of cell migration, dimerization and localization at the plasma membrane protrusions. Ref.6
Involvement in disease	A chromosomal aberration disrupting SRGAP2 has been found in a patient with early infantile epileptic encephalopathy. Balanced translocation t(1;9)(q32;q13).
Miscellaneous	There are 3 duplications of SRGAP2 in the human genome as a result of segmental gene duplications. SRGAP2C is the only one to be fixed at a diploid state in the human genome. Moreover, SRGAP2C is functional, interacts with and inhibits SRGAP2 and is human-specific. The appearance of SRGAP2C in the human genome is estimated to 2,4 million years ago, which corresponds to the beginning of neocortex expansion in human evolution and it may have played an important role in this process through its interaction with SRGAP2 function.
Sequence similarities	Contains 1 FCH domain. Contains 1 Rho-GAP domain. Contains 1 SH3 domain.
Sequence caution	The sequence BAA32301.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.

Ontologies

Keywords
Biological process	Neurogenesis
Cellular component	Cell junction Cell membrane Cell projection Cytoplasm Cytoplasmic vesicle Membrane Nucleus Postsynaptic cell membrane Synapse
Coding sequence diversity	Chromosomal rearrangement Polymorphism
Domain	Coiled coil SH3 domain
Molecular function	GTPase activation
PTM	Methylation Phosphoprotein
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	actin filament severing Inferred from direct assay Ref.10. Source: UniProtKB axon guidance Traceable author statement. Source: Reactome dendritic spine development Inferred from direct assay Ref.12. Source: UniProtKB extension of a leading process involved in cell motility in cerebral cortex radial glia guided migration Inferred from sequence or structural similarity. Source: UniProtKB filopodium assembly Inferred from direct assay Ref.12. Source: UniProtKB lamellipodium assembly involved in ameboidal cell migration Inferred from mutant phenotype Ref.6. Source: UniProtKB negative regulation of neuron migration Inferred from direct assay Ref.12. Source: UniProtKB small GTPase mediated signal transduction Traceable author statement. Source: Reactome substrate adhesion-dependent cell spreading Inferred from mutant phenotype Ref.6. Source: UniProtKB
Cellular_component	cell junction Inferred from electronic annotation. Source: UniProtKB-KW cytosol Inferred from sequence or structural similarity. Source: UniProtKB lamellipodium Inferred from direct assay Ref.6. Source: UniProtKB nucleus Inferred from electronic annotation. Source: UniProtKB-SubCell phagocytic vesicle Inferred from sequence or structural similarity. Source: UniProtKB plasma membrane Inferred from direct assay Ref.10. Source: UniProtKB postsynaptic density Inferred from sequence or structural similarity. Source: UniProtKB postsynaptic membrane Inferred from sequence or structural similarity. Source: UniProtKB
Molecular_function	Rac GTPase activator activity Inferred from direct assay Ref.10. Source: UniProtKB Rac GTPase binding Inferred from direct assay Ref.6Ref.10. Source: UniProtKB protein homodimerization activity Inferred from direct assay Ref.6. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
FMNL1	O95466	3	EBI-1051034,EBI-720020
PRMT5	O14744	4	EBI-1051034,EBI-351098

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 1071

1071

SLIT-ROBO Rho GTPase-activating protein 2

PRO_0000056767

Regions

Domain

22 – 87

66

FCH

Domain

489 – 679

191

Rho-GAP

Domain

728 – 787

60

SH3

Region

1 – 501

501

F-BAR domain

Coiled coil

362 – 401

40

Potential

Coiled coil

940 – 967

28

Potential

Compositional bias

843 – 909

67

Ser-rich

Amino acid modifications

Modified residue

799

1

Phosphoserine By similarity

Modified residue

927

1

Omega-N-methylated arginine; by PRMT5 Ref.6

Modified residue

930

1

Phosphoserine Ref.7

Natural variations

Natural variant

874

1

R → G.
Corresponds to variant rs17018890 [ dbSNP | Ensembl ].

VAR_055834

Experimental info

Mutagenesis

927

1

R → A: Loss of the ability to stimulate cell migration, to localize at the plasma membrane protrusions and to dimerize. Ref.6

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

1071

Helix Strand Turn

Details...

Beta strand

731 – 737

7

Beta strand

742 – 746

5

Beta strand

754 – 762

9

Beta strand

765 – 770

6

Beta strand

773 – 777

5

Beta strand

779 – 784

6

Sequences

	Sequence		Length	Mass (Da)
	O75044 [UniParc]. Last modified June 7, 2004. Version 2. Checksum: D8BC1939D6776312	FASTA	1,071	120,881
	10 20 30 40 50 60 MTSPAKFKKD KEIIAEYDTQ VKEIRAQLTE QMKCLDQQCE LRVQLLQDLQ DFFRKKAEIE 70 80 90 100 110 120 MDYSRNLEKL AERFLAKTRS TKDQQFKKDQ NVLSPVNCWN LLLNQVKRES RDHTTLSDIY 130 140 150 160 170 180 LNNIIPRFVQ VSEDSGRLFK KSKEVGQQLQ DDLMKVLNEL YSVMKTYHMY NADSISAQSK 190 200 210 220 230 240 LKEAEKQEEK QIGKSVKQED RQTPRSPDST ANVRIEEKHV RRSSVKKIEK MKEKRQAKYT 250 260 270 280 290 300 ENKLKAIKAR NEYLLALEAT NASVFKYYIH DLSDLIDQCC DLGYHASLNR ALRTFLSAEL 310 320 330 340 350 360 NLEQSKHEGL DAIENAVENL DATSDKQRLM EMYNNVFCPP MKFEFQPHMG DMASQLCAQQ 370 380 390 400 410 420 PVQSELVQRC QQLQSRLSTL KIENEEVKKT MEATLQTIQD IVTVEDFDVS DCFQYSNSME 430 440 450 460 470 480 SVKSTVSETF MSKPSIAKRR ANQQETEQFY FTKMKEYLEG RNLITKLQAK HDLLQKTLGE 490 500 510 520 530 540 SQRTDCSLAR RSSTVRKQDS SQAIPLVVES CIRFISRHGL QHEGIFRVSG SQVEVNDIKN 550 560 570 580 590 600 AFERGEDPLA GDQNDHDMDS IAGVLKLYFR GLEHPLFPKD IFHDLMACVT MDNLQERALH 610 620 630 640 650 660 IRKVLLVLPK TTLIIMRYLF AFLNHLSQFS EENMMDPYNL AICFGPSLMS VPEGHDQVSC 670 680 690 700 710 720 QAHVNELIKT IIIQHENIFP SPRELEGPVY SRGGSMEDYC DSPHGETTPV EDSTQDVTAE 730 740 750 760 770 780 HHTSDDECEP IEAIAKFDYV GRTARELSFK KGASLLLYQR ASDDWWEGRH NGIDGLIPHQ 790 800 810 820 830 840 YIVVQDTEDG VVERSSPKSE IEVISEPPEE KVTARAGASC PSGGHVADIY LANINKQRKR 850 860 870 880 890 900 PESGSIRKTF RSDSHGLSSS LTDSSSPGVG ASCRPSSQPI MSQSLPKEGP DKCSISGHGS 910 920 930 940 950 960 LNSISRHSSL KNRLDSPQIR KTATAGRSKS FNNHRPMDPE VIAQDIEATM NSALNELREL 970 980 990 1000 1010 1020 ERQSSVKHTP DVVLDTLEPL KTSPVVAPTS EPSSPLHTQL LKDPEPAFQR SASTAGDIAC 1030 1040 1050 1060 1070 AFRPVKSVKM AAPVKPPATR PKPTVFPKTN ATSPGVNSST SPQSTDKSCT V

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Characterization of cDNA clones in size-fractionated cDNA libraries from human brain." Seki N., Ohira M., Nagase T., Ishikawa K., Miyajima N., Nakajima D., Nomura N., Ohara O. DNA Res. 4:345-349(1997) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Brain.
[2]	"Signal transduction in neuronal migration: roles of GTPase activating proteins and the small GTPase Cdc42 in the Slit-Robo pathway." Wong K., Ren X.R., Huang Y.Z., Xie Y., Liu G., Saito H., Tang H., Wen L., Brady-Kalnay S.M., Mei L., Wu J.Y., Xiong W.C., Rao Y. Cell 107:209-221(2001) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH ROBO1.
[3]	"Global, in vivo, and site-specific phosphorylation dynamics in signaling networks." Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M. Cell 127:635-648(2006) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. Tissue: Cervix carcinoma.
[4]	"A quantitative atlas of mitotic phosphorylation." Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. Tissue: Cervix carcinoma.
[5]	"Identification of SH3 domain interaction partners of human FasL (CD178) by phage display screening." Voss M., Lettau M., Janssen O. BMC Immunol. 10:53-53(2009) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH FASLG.
[6]	"srGAP2 arginine methylation regulates cell migration and cell spreading through promoting dimerization." Guo S., Bao S. J. Biol. Chem. 285:35133-35141(2010) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN CELL MIGRATION, SUBCELLULAR LOCATION, INTERACTION WITH PRMT5, METHYLATION AT ARG-927 BY PRMT5, MUTAGENESIS OF ARG-927.
[7]	"Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis." Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M. Sci. Signal. 3:RA3-RA3(2010) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-930, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[8]	"Early infantile epileptic encephalopathy associated with the disrupted gene encoding Slit-Robo Rho GTPase activating protein 2 (SRGAP2)." Saitsu H., Osaka H., Sugiyama S., Kurosawa K., Mizuguchi T., Nishiyama K., Nishimura A., Tsurusaki Y., Doi H., Miyake N., Harada N., Kato M., Matsumoto N. Am. J. Med. Genet. A 158A:199-205(2012) [PubMed] [Europe PMC] [Abstract] Cited for: CHROMOSOMAL REARRANGEMENT.
[9]	"Initial characterization of the human central proteome." Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J. BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[10]	"Bi-modal regulation of a formin by srGAP2." Mason F.M., Heimsath E.G., Higgs H.N., Soderling S.H. J. Biol. Chem. 286:6577-6586(2011) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN ACTIN FILAMENT SEVERING, RAC1 GAP ACTIVITY, INTERACTION WITH FMNL1; FMNL3 AND ROBO2, SUBCELLULAR LOCATION.
[11]	"System-wide temporal characterization of the proteome and phosphoproteome of human embryonic stem cell differentiation." Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B. Sci. Signal. 4:RS3-RS3(2011) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[12]	"Inhibition of SRGAP2 function by its human-specific paralogs induces neoteny during spine maturation." Charrier C., Joshi K., Coutinho-Budd J., Kim J.E., Lambert N., de Marchena J., Jin W.L., Vanderhaeghen P., Ghosh A., Sassa T., Polleux F. Cell 149:923-935(2012) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH SRGAP2C.
[13]	"The F-BAR domains from srGAP1, srGAP2, and srGAP3 differentially regulate membrane deformation." Coutinho-Budd J., Ghukasyan V., Zylka M.J., Polleux F. J. Cell Sci. 125:3390-3401(2012) [PubMed] [Europe PMC] [Abstract] Cited for: HETEROOLIGOMERIZATION, DOMAIN F-BAR.
[14]	"Solution structure of the SH3 domain of human SLIT-ROBO Rho GTPase-activating protein 2." RIKEN structural genomics initiative (RSGI) Submitted (OCT-2006) to the PDB data bank Cited for: STRUCTURE BY NMR OF 729-787.
+	Additional computationally mapped references.

Web resources

Protein Spotlight

Branching out - Issue 143 of October 2012

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

AB007925 mRNA. Translation: BAA32301.1. Different initiation.

IPI

IPI00479125.

PIR

C59437.

RefSeq

NP_001164108.1. NM_001170637.2.
NP_056141.2. NM_015326.3.

UniGene

Hs.497575.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2DL8	NMR	-	A	729-787	[»]

ProteinModelPortal

O75044.

ModBase

Search...

Protein-protein interaction databases

IntAct

O75044. 13 interactions.

MINT

MINT-1682591.

STRING

9606.ENSP00000408089.

PTM databases

PhosphoSite

O75044.

Proteomic databases

PaxDb

O75044.

PRIDE

O75044.

Protocols and materials databases

DNASU

23380.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000414359; ENSP00000408089; ENSG00000163486.

GeneID

23380.

KEGG

hsa:23380.

Organism-specific databases

CTD

23380.

GeneCards

GC01P206516.

H-InvDB

HIX0001527.
HIX0029679.
HIX0116247.

HGNC

HGNC:19751. SRGAP2.

HPA

HPA028191.
HPA028196.

MIM

606524. gene.

neXtProt

NX_O75044.

PharmGKB

PA164742513.

HUGE

Search...

GenAtlas

Search...

Phylogenomic databases

eggNOG

NOG264793.

HOGENOM

HOG000039980.

HOVERGEN

HBG051637.

InParanoid

O75044.

KO

K07526.

Enzyme and pathway databases

Reactome

REACT_111045. Developmental Biology.
REACT_111102. Signal Transduction.
REACT_96538. Developmental Biology.

Gene expression databases

ArrayExpress

O75044.

Bgee

O75044.

CleanEx

HS_SRGAP2.

Genevestigator

O75044.

GermOnline

ENSG00000163486. Homo sapiens.

Family and domain databases

Gene3D

1.10.555.10. 1 hit.

InterPro

IPR001060. FCH_dom.
IPR008936. Rho_GTPase_activation_prot.
IPR000198. RhoGAP_dom.
IPR001452. SH3_domain.
[Graphical view]

Pfam

PF00611. FCH. 1 hit.
PF00620. RhoGAP. 1 hit.
PF00018. SH3_1. 1 hit.
[Graphical view]

SMART

SM00055. FCH. 1 hit.
SM00324. RhoGAP. 1 hit.
SM00326. SH3. 1 hit.
[Graphical view]

SUPFAM

SSF48350. Rho_GAP. 1 hit.
SSF50044. SH3. 1 hit.

PROSITE

PS50133. FCH. 1 hit.
PS50238. RHOGAP. 1 hit.
PS50002. SH3. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

ChiTaRS

SRGAP2. human.

EvolutionaryTrace

O75044.

GenomeRNAi

23380.

NextBio

45477.

SOURCE

Search...

Entry information

Entry name

SRGP2_HUMAN

Accession

Primary (citable) accession number: O75044

Entry history

Integrated into UniProtKB/Swiss-Prot:	June 7, 2004
Last sequence update:	June 7, 2004
Last modified:	May 1, 2013
This is version 113 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.