3b13
Crystal structure of the DHR-2 domain of DOCK2 in complex with Rac1 (T17N mutant)
Structural highlights
FunctionDOCK2_HUMAN Involved in cytoskeletal rearrangements required for lymphocyte migration in response of chemokines. Activates RAC1 and RAC2, but not CDC42, by functioning as a guanine nucleotide exchange factor (GEF), which exchanges bound GDP for free GTP. May also participate in IL2 transcriptional activation via the activation of RAC2.[1] Publication Abstract from PubMedDOCK2, a hematopoietic cell-specific, atypical guanine nucleotide exchange factor, controls lymphocyte migration through ras-related C3 botulinum toxin substrate (Rac) activation. Dedicator of cytokinesis 2-engulfment and cell motility protein 1 (DOCK2*ELMO1) complex formation is required for DOCK2-mediated Rac signaling. In this study, we identified the N-terminal 177-residue fragment and the C-terminal 196-residue fragment of human DOCK2 and ELMO1, respectively, as the mutual binding regions, and solved the crystal structure of their complex at 2.1-A resolution. The C-terminal Pro-rich tail of ELMO1 winds around the Src-homology 3 domain of DOCK2, and an intermolecular five-helix bundle is formed. Overall, the entire regions of both DOCK2 and ELMO1 assemble to create a rigid structure, which is required for the DOCK2*ELMO1 binding, as revealed by mutagenesis. Intriguingly, the DOCK2*ELMO1 interface hydrophobically buries a residue which, when mutated, reportedly relieves DOCK180 from autoinhibition. We demonstrated that the ELMO-interacting region and the DOCK-homology region 2 guanine nucleotide exchange factor domain of DOCK2 associate with each other for the autoinhibition, and that the assembly with ELMO1 weakens the interaction, relieving DOCK2 from the autoinhibition. The interactions between the N- and C-terminal regions of ELMO1 reportedly cause its autoinhibition, and binding with a DOCK protein relieves the autoinhibition for ras homolog gene family, member G binding and membrane localization. In fact, the DOCK2*ELMO1 interface also buries the ELMO1 residues required for the autoinhibition within the hydrophobic core of the helix bundle. Therefore, the present complex structure reveals the structural basis by which DOCK2 and ELMO1 mutually relieve their autoinhibition for the activation of Rac1 for lymphocyte chemotaxis. Structural basis for mutual relief of the Rac guanine nucleotide exchange factor DOCK2 and its partner ELMO1 from their autoinhibited forms.,Hanawa-Suetsugu K, Kukimoto-Niino M, Mishima-Tsumagari C, Akasaka R, Ohsawa N, Sekine S, Ito T, Tochio N, Koshiba S, Kigawa T, Terada T, Shirouzu M, Nishikimi A, Uruno T, Katakai T, Kinashi T, Kohda D, Fukui Y, Yokoyama S Proc Natl Acad Sci U S A. 2012 Feb 28;109(9):3305-10. Epub 2012 Feb 13. PMID:22331897[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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