SRGAP2

SLIT-ROBO Rho GTPase-activating protein 2 (srGAP2), also known as formin-binding protein 2 (FNBP2), is a mammalian protein that in humans is encoded by the SRGAP2 gene.[5][6] It is involved in neuronal migration and differentiation[7] and plays a critical role in synaptic development,[8] brain mass and number of cortical neurons.[9] Downregulation of srGAP2 inhibits cell–cell repulsion and enhances cell–cell contact duration.

SRGAP2
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesSRGAP2, ARHGAP34, FNBP2, SRGAP2A, SRGAP3, SLIT-ROBO Rho GTPase activating protein 2
External IDsOMIM: 606524 MGI: 109605 HomoloGene: 52683 GeneCards: SRGAP2
Orthologs
SpeciesHumanMouse
Entrez

23380

14270

Ensembl

ENSG00000266028

ENSMUSG00000026425

UniProt

O75044

Q91Z67

RefSeq (mRNA)

NM_001081011
NM_019520

RefSeq (protein)

NP_001074480

Location (UCSC)Chr 1: 206.2 – 206.46 MbChr 1: 131.21 – 131.46 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

SRGAP2 dimerizes through its F-BAR domain.[10] SRGAP2C, a shortened version found in early hominins and humans that only has the F-BAR domain, antagonizes its action. It slows maturation of some neurons and increases neuronal spine density.[10]

Evolution

SRGAP2 is one of 23 genes that are known to be duplicated in humans but not other primates.[11] SRGAP2 has been duplicated three times in the human genome in the past 3.4 million years: one duplication 3.4 million years ago (mya) called SRGAP2B, followed by two that copied SRGAP2B 2.4 mya into SRGAP2C and ~1 mya into SRGAP2D. All three duplications are also present in Denisovans and Neanderthals.[12] They are shortened in the same manner, keeping the F-box domain but ditching the RhoGAP and SH3 domains.[13] All humans possess SRGAP2C.[14] SRGAP2C inhibits the function of the ancestral copy, SRGAP2A, by heterodimerization and allows faster migration of neurons by interfering with filopodia production as well as slowing the rate of synaptic maturation and increasing the density of synapses in the cerebral cortex.[8] SRGAP2B is expressed at very low levels, and SRGAP2D is a pseudogene. Not all humans have SRGAP2B or SRGAP2D.[13]

References
  1. GRCh38: Ensembl release 89: ENSG00000266028 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000026425 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. Madura T, Yamashita T, Kubo T, Tsuji L, Hosokawa K, Tohyama M (April 2004). "Changes in mRNA of Slit-Robo GTPase-activating protein 2 following facial nerve transection". Brain Research. Molecular Brain Research. 123 (1–2): 76–80. doi:10.1016/j.molbrainres.2004.01.002. PMID 15046868.
  6. Wong K, Ren XR, Huang YZ, Xie Y, Liu G, Saito H, Tang H, Wen L, Brady-Kalnay SM, Mei L, Wu JY, Xiong WC, Rao Y (October 2001). "Signal transduction in neuronal migration: roles of GTPase activating proteins and the small GTPase Cdc42 in the Slit-Robo pathway". Cell. 107 (2): 209–21. doi:10.1016/S0092-8674(01)00530-X. PMID 11672528. S2CID 2458943.
  7. Guerrier S, Coutinho-Budd J, Sassa T, Gresset A, Jordan NV, Chen K, Jin WL, Frost A, Polleux F (September 2009). "The F-BAR domain of srGAP2 induces membrane protrusions required for neuronal migration and morphogenesis". Cell. 138 (5): 990–1004. doi:10.1016/j.cell.2009.06.047. PMC 2797480. PMID 19737524.
  8. Charrier C, Joshi K, Coutinho-Budd J, Kim JE, Lambert N, de Marchena J, Jin WL, Vanderhaeghen P, Ghosh A, Sassa T, Polleux F (May 2012). "Inhibition of SRGAP2 function by its human-specific paralogs induces neoteny during spine maturation". Cell. 149 (4): 923–35. doi:10.1016/j.cell.2012.03.034. PMC 3357949. PMID 22559944.
  9. Tiwary, BK (2016). "Evolution of the SRGAP2 gene is linked to intelligence in mammals". Biomedicine Hub. Karger. 1 (1): 1–12. doi:10.1159/000443947. PMC 6945801. PMID 31988884.
  10. Chang, Hsin-Yu. "What's ape". InterPro Blog. Retrieved 27 March 2019.
  11. Sudmant PH, Kitzman JO, Antonacci F, Alkan C, Malig M, Tsalenko A, Sampas N, Bruhn L, Shendure J, Eichler EE (October 2010). "Diversity of human copy number variation and multicopy genes". Science. 330 (6004): 641–6. Bibcode:2010Sci...330..641S. doi:10.1126/science.1197005. PMC 3020103. PMID 21030649.
  12. Martins, Pedro Tiago; Marí, Maties; Boeckx, Cedric (2018-01-01). "SRGAP2 and the gradual evolution of the modern human language faculty". Journal of Language Evolution. 3 (1): 67–78. doi:10.1093/jole/lzx020. ISSN 2058-4571.
  13. Sporny, M; Guez-Haddad, J; Kreusch, A; Shakartzi, S; Neznansky, A; Cross, A; Isupov, MN; Qualmann, B; Kessels, MM; Opatowsky, Y (1 June 2017). "Structural History of Human SRGAP2 Proteins". Molecular Biology and Evolution. 34 (6): 1463–1478. doi:10.1093/molbev/msx094. PMC 5435084. PMID 28333212.
  14. Dennis MY, Nuttle X, Sudmant PH, Antonacci F, Graves TA, Nefedov M, Rosenfeld JA, Sajjadian S, Malig M, Kotkiewicz H, Curry CJ, Shafer S, Shaffer LG, de Jong PJ, Wilson RK, Eichler EE (May 2012). "Evolution of human-specific neural SRGAP2 genes by incomplete segmental duplication". Cell. 149 (4): 912–22. doi:10.1016/j.cell.2012.03.033. PMC 3365555. PMID 22559943.
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