| Structural highlights
Function
DOC10_MOUSE Guanine nucleotide-exchange factor (GEF) that activates CDC42 and RAC1 by exchanging bound GDP for free GTP. Essential for dendritic spine morphogenesis in Purkinje cells and in hippocampal neurons, via a CDC42-mediated pathway (PubMed:25851601). Sustains B-cell lymphopoiesis in secondary lymphoid tissues and regulates FCER2/CD23 expression (PubMed:27502165).[1] [2]
Publication Abstract from PubMed
Dedicator of cytokinesis 10 (DOCK10), an evolutionarily conserved guanine nucleotide exchange factor (GEF) for Rho GTPases, has the unique specificity within the DOCK-D subfamily to activate both Cdc42 and Rac, but the structural bases for these activities remained unknown. Here we present the crystal structures of the catalytic DHR2 domain of mouse DOCK10, complexed with either Cdc42 or Rac1. The structures revealed that DOCK10(DHR2) binds to Cdc42 or Rac1 by slightly changing the arrangement of its two catalytic lobes. DOCK10 also has a flexible binding pocket for the 56th GTPase residue, allowing a novel interaction with Trp56(Rac1). The conserved residues in switch 1 of Cdc42 and Rac1 showed common interactions with the unique Lys-His sequence in the beta5/beta6 loop of DOCK10(DHR2). However, the interaction of switch 1 in Rac1 was less stable than that of switch 1 in Cdc42, due to amino acid differences at positions 27 and 30. Structure-based mutagenesis identified the DOCK10 residues that determine the Cdc42/Rac1 dual specificity.
Structural basis for the dual GTPase specificity of the DOCK10 guanine nucleotide exchange factor.,Kukimoto-Niino M, Ihara K, Mishima-Tsumagari C, Inoue M, Fukui Y, Yokoyama S, Shirouzu M Biochem Biophys Res Commun. 2023 Apr 23;653:12-20. doi: , 10.1016/j.bbrc.2023.02.054. Epub 2023 Feb 21. PMID:36848820[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Jaudon F, Raynaud F, Wehrlé R, Bellanger JM, Doulazmi M, Vodjdani G, Gasman S, Fagni L, Dusart I, Debant A, Schmidt S. The RhoGEF DOCK10 is essential for dendritic spine morphogenesis. Mol Biol Cell. 2015 Jun 1;26(11):2112-27. PMID:25851601 doi:10.1091/mbc.E14-08-1310
- ↑ García-Serna AM, Alcaraz-García MJ, Ruiz-Lafuente N, Sebastián-Ruiz S, Martínez CM, Moya-Quiles MR, Minguela A, García-Alonso AM, Martín-Orozco E, Parrado A. Dock10 regulates CD23 expression and sustains B-cell lymphopoiesis in secondary lymphoid tissue. Immunobiology. 2016 Dec;221(12):1343-1350. PMID:27502165 doi:10.1016/j.imbio.2016.07.015
- ↑ Kukimoto-Niino M, Ihara K, Mishima-Tsumagari C, Inoue M, Fukui Y, Yokoyama S, Shirouzu M. Structural basis for the dual GTPase specificity of the DOCK10 guanine nucleotide exchange factor. Biochem Biophys Res Commun. 2023 Apr 23;653:12-20. PMID:36848820 doi:10.1016/j.bbrc.2023.02.054
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