RHO to the DOCK for GDP disembarking: Structural insights into the DOCK GTPase nucleotide exchange factors
| Autor: | J.L. Gray, Christina Bitsina, Frank von Delft, Paul Brennan, Andrew P. Thompson |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Protein Conformation aPKC atypical protein kinase dedicator of cytokinesis (DOCK) GTPase Biology guanosine triphosphate (GTP) Ras homologous (RHO) small GTPases AD Alzheimer’s disease Biochemistry PAK p21-activated kinase drug discovery GTP Phosphohydrolases GEF guanine nucleotide exchange factor 03 medical and health sciences GTP guanosine triphosphate APP amyloid precursor protein DOCK Catalytic Domain MRCK myotonic dystrophy kinase-related CDC42-binding kinase guanine nucleotide exchange factor cell signaling structural biology Cytoskeleton Molecular Biology GDP guanosine diphosphate 030102 biochemistry & molecular biology Drug discovery DHR2 domain JBC Reviews GDI GDP dissociation inhibitor Cell Biology CDOCK dedicator of cytokinesis Cell biology 030104 developmental biology Structural biology Guanine nucleotide exchange factor Cytokinesis Rho Guanine Nucleotide Exchange Factors |
| Zdroj: | The Journal of Biological Chemistry |
| ISSN: | 1083-351X 0021-9258 |
| Popis: | The human dedicator of cytokinesis (DOCK) family consists of 11 structurally conserved proteins that serve as atypical RHO guanine nucleotide exchange factors (RHO GEFs). These regulatory proteins act as mediators in numerous cellular cascades that promote cytoskeletal remodeling, playing roles in various crucial processes such as differentiation, migration, polarization, and axon growth in neurons. At the molecular level, DOCK DHR2 domains facilitate nucleotide dissociation from small GTPases, a process that is otherwise too slow for rapid spatiotemporal control of cellular signaling. Here, we provide an overview of the biological and structural characteristics for the various DOCK proteins and describe how they differ from other RHO GEFs and between DOCK subfamilies. The expression of the family varies depending on cell or tissue type, and they are consequently implicated in a broad range of disease phenotypes, particularly in the brain. A growing body of available structural information reveals the mechanism by which the catalytic DHR2 domain elicits nucleotide dissociation and also indicates strategies for the discovery and design of high-affinity small-molecule inhibitors. Such compounds could serve as chemical probes to interrogate the cellular function and provide starting points for drug discovery of this important class of enzymes. |
| Databáze: | OpenAIRE |
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