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Structural biology of DOCK‐family guanine nucleotide exchange factors
Author(s) -
Boland Andreas,
Côté JeanFrancois,
Barford David
Publication year - 2023
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1002/1873-3468.14523
Subject(s) - dock , guanine nucleotide exchange factor , gtpase , cdc42 , biology , microbiology and biotechnology , biochemistry
DOCK proteins are a family of multi‐domain guanine nucleotide exchange factors (GEFs) that activate the RHO GTPases CDC42 and RAC1, thereby regulating several RHO GTPase‐dependent cellular processes. DOCK proteins are characterized by the catalytic DHR2 domain (DOCK DHR2 ), and a phosphatidylinositol(3,4,5)P 3 ‐binding DHR1 domain (DOCK DHR1 ) that targets DOCK proteins to plasma membranes. DOCK‐family GEFs are divided into four subfamilies (A to D) differing in their specificities for CDC42 and RAC1, and the composition of accessory signalling domains. Additionally, the DOCK‐A and DOCK‐B subfamilies are constitutively associated with ELMO proteins that auto‐inhibit DOCK GEF activity. We review structural studies that have provided mechanistic insights into DOCK‐protein functions. These studies revealed how a conserved nucleotide sensor in DOCK DHR2 catalyses nucleotide exchange, the basis for how different DOCK proteins activate specifically CDC42 and RAC1, and sometimes both, and how up‐stream regulators relieve the ELMO‐mediated auto‐inhibition. We conclude by presenting a model for full‐length DOCK9 of the DOCK‐D subfamily. The involvement of DOCK GEFs in a range of diseases highlights the importance of gaining structural insights into these proteins to better understand and specifically target them.