2NZ8

N-terminal DHPH cassette of Trio in complex with nucleotide-free Rac1

2NZ8 の概要

• エントリーDOI: 10.2210/pdb2nz8/pdb
• 分子名称: ras-related C3 botulinum toxin substrate 1 isoform Rac1, triple functional domain protein (3 entities in total)
• 機能のキーワード: trio; rac1; dbl-family gef; rho-family gtpase; dh/ph cassette, signaling protein, cell cycle
• 由来する生物種: Homo sapiens (human); 詳細
• 細胞内の位置: Cell membrane ; Lipid-anchor ; Cytoplasmic side : P63000; Cytoplasm : O75962
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 56272.72

構造登録者

Chhatriwala, M.K.,Betts, L.,Worthylake, D.K.,Sondek, J. (登録日: 2006-11-22, 公開日: 2007-04-10, 最終更新日: 2023-08-30)

主引用文献

Chhatriwala, M.K.,Betts, L.,Worthylake, D.K.,Sondek, J.
The DH and PH Domains of Trio Coordinately Engage Rho GTPases for their Efficient Activation
J.Mol.Biol., 368:1307-1320, 2007

PubMed Abstract: Rho-family GTPases are activated by the exchange of bound GDP for GTP, a process that is catalyzed by Dbl-family guanine nucleotide exchange factors (GEFs). The catalytic unit of Dbl-family GEFs consists of a Dbl homology (DH) domain followed almost invariantly by a pleckstrin-homology (PH) domain. The majority of the catalytic interface forms between the switch regions of the GTPase and the DH domain, but full catalytic activity often requires the associated PH domain. Although PH domains are usually characterized as lipid-binding regions, they also participate in protein-protein interactions. For example, the DH-associated PH domain of Dbs must contact its cognate GTPases for efficient exchange. Similarly, the N-terminal DH/PH fragment of Trio, which catalyzes exchange on both Rac1 and RhoG, is fourfold more active in vitro than the isolated DH domain. Given continued uncertainty regarding functional roles of DH-associated PH domains, we have undertaken structural and functional analyses of the N-terminal DH/PH cassette of Trio. The crystal structure of this fragment of Trio bound to nucleotide-depleted Rac1 highlights the engagement of the PH domain with Rac1 and substitution of residues involved in this interface substantially diminishes activation of Rac1 and RhoG. Also, these mutations significantly reduce the ability of full-length Trio to induce neurite outgrowth dependent on RhoG activation in PC-12 cells. Overall, these studies substantiate a general role for DH-associated PH domains in engaging Rho GTPases directly for efficient guanine nucleotide exchange and support a parsimonious explanation for the essentially invariant linkage between DH and PH domains.

PubMed: 17391702
DOI: 10.1016/j.jmb.2007.02.060

実験手法

X-RAY DIFFRACTION (2 Å)