SRG2C_HUMAN
ID SRG2C_HUMAN Reviewed; 459 AA.
AC P0DJJ0;
DT 11-JUL-2012, integrated into UniProtKB/Swiss-Prot.
DT 11-JUL-2012, sequence version 1.
DT 03-AUG-2022, entry version 66.
DE RecName: Full=SLIT-ROBO Rho GTPase-activating protein 2C {ECO:0000303|PubMed:22559944};
DE AltName: Full=SLIT-ROBO Rho GTPase activating protein 2 pseudogene 1;
GN Name=SRGAP2C {ECO:0000303|PubMed:22559944, ECO:0000312|HGNC:HGNC:30584};
GN Synonyms=SRGAP2P1 {ECO:0000312|HGNC:HGNC:30584};
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, TISSUE SPECIFICITY, HOMODIMERIZATION,
RP AND INTERACTION WITH SRGAP2.
RX PubMed=22559944; DOI=10.1016/j.cell.2012.03.034;
RA Charrier C., Joshi K., Coutinho-Budd J., Kim J.E., Lambert N.,
RA de Marchena J., Jin W.L., Vanderhaeghen P., Ghosh A., Sassa T., Polleux F.;
RT "Inhibition of SRGAP2 function by its human-specific paralogs induces
RT neoteny during spine maturation.";
RL Cell 149:923-935(2012).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A.,
RA Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C.,
RA Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K.,
RA Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C.,
RA Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W.,
RA Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J.,
RA Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J.,
RA Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y.,
RA Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J.,
RA Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S.,
RA Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K.,
RA Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R.,
RA Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M.,
RA Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S.,
RA Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J.,
RA Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W.,
RA McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S.,
RA Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M.,
RA White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H.,
RA Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E.,
RA Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G.,
RA Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Mammary carcinoma;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP IDENTIFICATION, CHROMOSOMAL LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=22559943; DOI=10.1016/j.cell.2012.03.033;
RA Dennis M.Y., Nuttle X., Sudmant P.H., Antonacci F., Graves T.A.,
RA Nefedov M., Rosenfeld J.A., Sajjadian S., Malig M., Kotkiewicz H.,
RA Curry C.J., Shafer S., Shaffer L.G., de Jong P.J., Wilson R.K.,
RA Eichler E.E.;
RT "Evolution of human-specific neural SRGAP2 genes by incomplete segmental
RT duplication.";
RL Cell 149:912-922(2012).
RN [5]
RP FUNCTION.
RX PubMed=27373832; DOI=10.1016/j.neuron.2016.06.013;
RA Fossati M., Pizzarelli R., Schmidt E.R., Kupferman J.V., Stroebel D.,
RA Polleux F., Charrier C.;
RT "SRGAP2 and its human-specific paralog co-regulate the development of
RT excitatory and inhibitory synapses.";
RL Neuron 91:356-369(2016).
RN [6]
RP FUNCTION, DOMAIN, INTERACTION WITH SRGAP2, AND MUTAGENESIS OF HIS-73;
RP TRP-108; CYS-205; HIS-235 AND GLN-250.
RX PubMed=28333212; DOI=10.1093/molbev/msx094;
RA Sporny M., Guez-Haddad J., Kreusch A., Shakartzi S., Neznansky A.,
RA Cross A., Isupov M.N., Qualmann B., Kessels M.M., Opatowsky Y.;
RT "Structural history of human SRGAP2 proteins.";
RL Mol. Biol. Evol. 34:1463-1478(2017).
RN [7]
RP IDENTIFICATION.
RX PubMed=28580430; DOI=10.1038/s41559-016-0069;
RA Dennis M.Y., Harshman L., Nelson B.J., Penn O., Cantsilieris S.,
RA Huddleston J., Antonacci F., Penewit K., Denman L., Raja A., Baker C.,
RA Mark K., Malig M., Janke N., Espinoza C., Stessman H.A.F., Nuttle X.,
RA Hoekzema K., Lindsay-Graves T.A., Wilson R.K., Eichler E.E.;
RT "The evolution and population diversity of human-specific segmental
RT duplications.";
RL Nat. Ecol. Evol. 1:69-69(2017).
RN [8]
RP FUNCTION, AND INTERACTION WITH SRGAP2.
RX PubMed=31822692; DOI=10.1038/s41598-019-54887-4;
RA Schmidt E.R.E., Kupferman J.V., Stackmann M., Polleux F.;
RT "The human-specific paralogs SRGAP2B and SRGAP2C differentially modulate
RT SRGAP2A-dependent synaptic development.";
RL Sci. Rep. 9:18692-18692(2019).
RN [9]
RP FUNCTION.
RX PubMed=34707291; DOI=10.1038/s41586-021-04039-4;
RA Schmidt E.R.E., Zhao H.T., Park J.M., Dipoppa M., Monsalve-Mercado M.M.,
RA Dahan J.B., Rodgers C.C., Lejeune A., Hillman E.M.C., Miller K.D.,
RA Bruno R.M., Polleux F.;
RT "A human-specific modifier of cortical connectivity and circuit function.";
RL Nature 599:640-644(2021).
CC -!- FUNCTION: Human-specific protein that acts as a key modifier of
CC cortical connectivity in the human brain (PubMed:22559944,
CC PubMed:27373832, PubMed:34707291). Acts by inhibiting the functions of
CC ancestral paralog SRGAP2/SRGAP2A, a postsynaptic protein that regulates
CC excitatory and inhibitory synapse maturation and density in cortical
CC pyramidal neurons (PubMed:22559944, PubMed:27373832). SRGAP2C is
CC unstable but is able to heterodimerize with SRGAP2/SRGAP2A, thereby
CC reducing SRGAP2/SRGAP2A levels through proteasome-dependent degradation
CC (PubMed:27373832, PubMed:28333212, PubMed:31822692). Inhibition of
CC SRGAP2/SRGAP2A by SRGAP2C leads to an increase in synaptic density and
CC protracted synaptic maturation of both excitatory and inhibitory
CC synapses (PubMed:27373832, PubMed:34707291). Modifies cortical circuit
CC connectivity by increasing the number of local and long-range cortical
CC inputs received by layer 2/3 pyramidal neurons (PubMed:34707291). Also
CC able to increase the probability of sensory-evoked responses by layer
CC 2/3 pyramidal neurons (PubMed:34707291). {ECO:0000269|PubMed:22559944,
CC ECO:0000269|PubMed:27373832, ECO:0000269|PubMed:28333212,
CC ECO:0000269|PubMed:31822692, ECO:0000269|PubMed:34707291}.
CC -!- SUBUNIT: Homodimer (PubMed:22559944). Interacts (via F-BAR domain) with
CC SRGAP2/SRGAP2A (via F-BAR domain); formation of the heterodimer
CC inhibits SRGAP2/SRGAP2A function (PubMed:22559944, PubMed:28333212,
CC PubMed:34707291). {ECO:0000269|PubMed:22559944,
CC ECO:0000269|PubMed:28333212, ECO:0000269|PubMed:34707291}.
CC -!- TISSUE SPECIFICITY: Ubiquitously expressed with higher expression in
CC cerebellum (PubMed:22559943, PubMed:22559944). Probably expressed in
CC fetal and adult neurons (at protein level) (PubMed:22559943).
CC {ECO:0000269|PubMed:22559943, ECO:0000269|PubMed:22559944}.
CC -!- DOMAIN: SRGAP2C is truncated at its C-terminus compared to
CC SRGAP2/SRGAP2A (PubMed:28333212). It only contains an extended F-BAR
CC domain that lacks the last C-terminal 49 amino acids of SRGAP2/SRGAP2A,
CC which are replaced with seven unique C-terminal amino acids
CC (PubMed:28333212). In addition, SRGAP2C acquired a series of unique
CC nonsynonymous base pair mutations selectively targeting five arginine
CC residues compared to SRGAP2B (PubMed:28333212). This truncation and
CC these specific arginine mutations reduce solubility of SRGAP2C and
CC increase its ability to heterodimerize with SRGAP2/SRGAP2A to form an
CC insoluble complex (PubMed:28333212). {ECO:0000269|PubMed:28333212}.
CC -!- MISCELLANEOUS: This is one of the 3 duplications of the ancestral gene
CC SRGAP2/SRGAP2A which has undergone human-specific segmental gene
CC duplications (PubMed:22559944, PubMed:22559943). The appearance of
CC SRGAP2C in the human genome is estimated to 2,4 million years and
CC corresponds to the beginning of neocortex expansion in human evolution
CC (PubMed:22559944, PubMed:22559943, PubMed:34707291). The emergence of
CC SRGAP2C at the birth of the Homo lineage probably contributed to the
CC evolution of specific structural and functional features of cortical
CC circuits in the human cortex (PubMed:34707291).
CC {ECO:0000269|PubMed:22559943, ECO:0000269|PubMed:22559944,
CC ECO:0000269|PubMed:34707291}.
CC -!- MISCELLANEOUS: Expression of SRGAP2C in mouse cortical pyramidal
CC neurons leads to the emergence of human-specific traits of synaptic
CC development, characterized by increases in the density of both
CC excitatory and inhibitory synapses received by layer 2/3 pyramidal
CC neurons and neotenic features of excitatory and inhibitory synaptic
CC development (PubMed:22559944, PubMed:27373832, PubMed:34707291). Mice
CC humanized for SRGAP2C expression in all cortical pyramidal neurons show
CC a shift in the fraction of layer 2/3 pyramidal neurons activated by
CC sensory stimulation and an enhanced ability to learn a cortex-dependent
CC sensory-discrimination task (PubMed:34707291).
CC {ECO:0000269|PubMed:22559944, ECO:0000269|PubMed:27373832,
CC ECO:0000269|PubMed:34707291}.
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DR EMBL; AC243994; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC244021; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC244453; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC112927; -; NOT_ANNOTATED_CDS; mRNA.
DR CCDS; CCDS81364.1; -.
DR RefSeq; NP_001316913.1; NM_001329984.1.
DR AlphaFoldDB; P0DJJ0; -.
DR SMR; P0DJJ0; -.
DR IntAct; P0DJJ0; 1.
DR STRING; 9606.ENSP00000478290; -.
DR iPTMnet; P0DJJ0; -.
DR PhosphoSitePlus; P0DJJ0; -.
DR BioMuta; SRGAP2C; -.
DR DMDM; 395455176; -.
DR EPD; P0DJJ0; -.
DR jPOST; P0DJJ0; -.
DR MassIVE; P0DJJ0; -.
DR MaxQB; P0DJJ0; -.
DR PeptideAtlas; P0DJJ0; -.
DR PRIDE; P0DJJ0; -.
DR ProteomicsDB; 52551; -.
DR Antibodypedia; 77326; 28 antibodies from 5 providers.
DR DNASU; 653464; -.
DR Ensembl; ENST00000367123.8; ENSP00000478290.1; ENSG00000171943.12.
DR GeneID; 653464; -.
DR KEGG; hsa:653464; -.
DR MANE-Select; ENST00000367123.8; ENSP00000478290.1; NM_001329984.2; NP_001316913.1.
DR UCSC; uc057jxs.1; human.
DR CTD; 653464; -.
DR DisGeNET; 653464; -.
DR GeneCards; SRGAP2C; -.
DR HGNC; HGNC:30584; SRGAP2C.
DR HPA; ENSG00000171943; Tissue enhanced (brain).
DR MIM; 614704; gene.
DR neXtProt; NX_P0DJJ0; -.
DR OpenTargets; ENSG00000171943; -.
DR VEuPathDB; HostDB:ENSG00000171943; -.
DR eggNOG; KOG3565; Eukaryota.
DR GeneTree; ENSGT00950000182824; -.
DR HOGENOM; CLU_005715_1_0_1; -.
DR InParanoid; P0DJJ0; -.
DR OMA; ETEIFYI; -.
DR PathwayCommons; P0DJJ0; -.
DR SignaLink; P0DJJ0; -.
DR BioGRID-ORCS; 653464; 21 hits in 137 CRISPR screens.
DR ChiTaRS; SRGAP2C; human.
DR GeneWiki; SRGAP2C; -.
DR GenomeRNAi; 653464; -.
DR Pharos; P0DJJ0; Tbio.
DR PRO; PR:P0DJJ0; -.
DR Proteomes; UP000005640; Chromosome 1.
DR RNAct; P0DJJ0; protein.
DR Bgee; ENSG00000171943; Expressed in ventricular zone and 109 other tissues.
DR ExpressionAtlas; P0DJJ0; baseline and differential.
DR Genevisible; P0DJJ0; HS.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0046982; F:protein heterodimerization activity; IPI:UniProtKB.
DR GO; GO:0042803; F:protein homodimerization activity; IPI:UniProtKB.
DR GO; GO:0021987; P:cerebral cortex development; IDA:UniProtKB.
DR GO; GO:1904861; P:excitatory synapse assembly; IDA:UniProtKB.
DR GO; GO:0021816; P:extension of a leading process involved in cell motility in cerebral cortex radial glia guided migration; IDA:UniProtKB.
DR GO; GO:1904862; P:inhibitory synapse assembly; IDA:UniProtKB.
DR GO; GO:0030336; P:negative regulation of cell migration; IBA:GO_Central.
DR GO; GO:0061000; P:negative regulation of dendritic spine development; IDA:UniProtKB.
DR GO; GO:0051490; P:negative regulation of filopodium assembly; IDA:UniProtKB.
DR GO; GO:2001224; P:positive regulation of neuron migration; IDA:UniProtKB.
DR Gene3D; 1.20.1270.60; -; 1.
DR InterPro; IPR027267; AH/BAR_dom_sf.
DR InterPro; IPR031160; F_BAR.
DR InterPro; IPR001060; FCH_dom.
DR InterPro; IPR030252; srGAP2.
DR PANTHER; PTHR14166:SF6; PTHR14166:SF6; 1.
DR Pfam; PF00611; FCH; 1.
DR SMART; SM00055; FCH; 1.
DR SUPFAM; SSF103657; SSF103657; 1.
DR PROSITE; PS51741; F_BAR; 1.
PE 1: Evidence at protein level;
KW Coiled coil; Neurogenesis; Reference proteome.
FT CHAIN 1..459
FT /note="SLIT-ROBO Rho GTPase-activating protein 2C"
FT /id="PRO_0000418193"
FT DOMAIN 22..325
FT /note="F-BAR"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01077"
FT REGION 181..211
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COILED 363..401
FT /evidence="ECO:0000255"
FT COMPBIAS 181..197
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MUTAGEN 73
FT /note="H->R: Does not improve solubility; when associated
FT with R-108, R-205, R-235 and R-250."
FT /evidence="ECO:0000269|PubMed:28333212"
FT MUTAGEN 108
FT /note="W->R: Does not improve solubility; when associated
FT with R-73, R-205, R-235 and R-250."
FT /evidence="ECO:0000269|PubMed:28333212"
FT MUTAGEN 205
FT /note="C->R: Does not improve solubility; when associated
FT with R-73, R-108, R-235 and R-250."
FT /evidence="ECO:0000269|PubMed:28333212"
FT MUTAGEN 235
FT /note="H->R: Does not improve solubility; when associated
FT with R-73, R-108, R-205 and R-250."
FT /evidence="ECO:0000269|PubMed:28333212"
FT MUTAGEN 250
FT /note="Q->R: Does not improve solubility; when associated
FT with R-73, R-108, R-205 and R-235."
FT /evidence="ECO:0000269|PubMed:28333212"
FT CONFLICT 278
FT /note="Missing (in Ref. 3; BC112927)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 459 AA; 53484 MW; 3FBAC28FE3C43297 CRC64;
MTSPAKFKKD KEIIAEYDTQ VKEIRAQLTE QMKCLDQQCE LRVQLLQDLQ DFFRKKAEIE
MDYSRNLEKL AEHFLAKTRS TKDQQFKKDQ NVLSPVNCWN LLLNQVKWES RDHTTLSDIY
LNNIIPRFVQ VSEDSGRLFK KSKEVGQQLQ DDLMKVLNEL YSVMKTYHMY NADSISAQSK
LKEAEKQEEK QIGKSVKQED RQTPCSPDST ANVRIEEKHV RRSSVKKIEK MKEKHQAKYT
ENKLKAIKAQ NEYLLALEAT NASVFKYYIH DLSDLIDQCC DLGYHASLNR ALRTFLSAEL
NLEQSKHEGL DAIENAVENL DATSDKQRLM EMYNNVFCPP MKFEFQPHMG DMASQLCAQQ
PVQSELVQRC QQLQSRLSTL KIENEEVKKT MEATLQTIQD IVTVEDFDVS DCFQYSNSME
SVKSTVSETF MSKPSIAKRR ANQQETEQFY FTVRECYGF
