Structural basis for mutual relief of the Rac guanine nucleotide exchange factor DOCK2 and its partner ELMO1 from their autoinhibited forms

Kyoko Hanawa-Suetsugu, Mutsuko Kukimoto-Niino, Chiemi Mishima-Tsumagari, Ryogo Akasaka, Noboru Ohsawa, Shun Ichi Sekine, Takuhiro Ito, Naoya Tochio, Seizo Koshiba, Takanori Kigawa, Takaho Terada, Mikako Shirouzu, Akihiko Nishikimi, Takehito Uruno, Tomoya Katakai, Tatsuo Kinashi, Daisuke Kohda, Yoshinori Fukui, Shigeyuki Yokoyama

研究成果: Article

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DOCK2, 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-Å resolution. The C-terminal Prorich 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.

元の言語English
ページ(範囲)3305-3310
ページ数6
ジャーナルProceedings of the National Academy of Sciences of the United States of America
109
発行部数9
DOI
出版物ステータスPublished - 2012 2 28

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フィンガープリント Structural basis for mutual relief of the Rac guanine nucleotide exchange factor DOCK2 and its partner ELMO1 from their autoinhibited forms' の研究トピックを掘り下げます。これらはともに一意のフィンガープリントを構成します。

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    Hanawa-Suetsugu, K., Kukimoto-Niino, M., Mishima-Tsumagari, C., Akasaka, R., Ohsawa, N., Sekine, S. I., 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. (2012). Structural basis for mutual relief of the Rac guanine nucleotide exchange factor DOCK2 and its partner ELMO1 from their autoinhibited forms. Proceedings of the National Academy of Sciences of the United States of America, 109(9), 3305-3310. https://doi.org/10.1073/pnas.1113512109