AI Article Synopsis
- DOCK proteins are guanine nucleotide exchange factors (GEFs) that activate RHO GTPases CDC42 and RAC1, playing a key role in controlling various cellular processes.
- There are four subfamilies of DOCK proteins (A to D), each with different affinities for CDC42 and RAC1, and some are associated with ELMO proteins that auto-inhibit their activity.
- Structural studies have improved our understanding of how DOCK proteins function, including mechanisms of nucleotide exchange and regulation, which is crucial for developing targeted therapies for diseases linked to DOCK GEFs.
Article Abstract
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 ), and a phosphatidylinositol(3,4,5)P -binding DHR1 domain (DOCK ) 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 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.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10152721 | PMC |
| http://dx.doi.org/10.1002/1873-3468.14523 | DOI Listing |
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