Structural Biology of DOCK-family Guanine Nucleotide Exchange Factors

Overview

Journal FEBS Lett

Specialty Biochemistry

Date 2022 Oct 22

PMID 36271211

Authors

Andreas Boland

Jean-Francois Cote

David Barford

Affiliations

Soon will be listed here.

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.

Citing Articles

Lipid nanoparticle-encapsulated DOCK11-siRNA efficiently reduces hepatitis B virus cccDNA level in infected mice.

Okada H, Sakamoto T, Nio K, Li Y, Kuroki K, Sugimoto S Mol Ther Methods Clin Dev. 2024; 32(3):101289.

PMID: 39109217 PMC: 11300937. DOI: 10.1016/j.omtm.2024.101289.

CED-5/CED-12 (DOCK/ELMO) can promote and inhibit F-actin formation via distinct motifs that may target different GTPases.

Venkatachalam T, Mannimala S, Pulijala Y, Soto M PLoS Genet. 2024; 20(7):e1011330.

PMID: 39083711 PMC: 11290852. DOI: 10.1371/journal.pgen.1011330.

Refinement of rice blast disease resistance QTLs and gene networks through meta-QTL analysis.

Devanna B, Sucharita S, Sunitha N, Anilkumar C, Singh P, Pramesh D Sci Rep. 2024; 14(1):16458.

PMID: 39013915 PMC: 11252161. DOI: 10.1038/s41598-024-64142-0.

Roles Played by DOCK11, a Guanine Nucleotide Exchange Factor, in HBV Entry and Persistence in Hepatocytes.

Li Y, Murai K, Lyu J, Honda M Viruses. 2024; 16(5).

PMID: 38793626 PMC: 11125634. DOI: 10.3390/v16050745.

Mapping the MOB proteins' proximity network reveals a unique interaction between human MOB3C and the RNase P complex.

Elkholi I, Boulais J, Thibault M, Phan H, Robert A, Lai L J Biol Chem. 2023; 299(9):105123.

PMID: 37536630 PMC: 10480535. DOI: 10.1016/j.jbc.2023.105123.

References

Lu M, Kinchen J, Rossman K, Grimsley C, Hall M, Sondek J . A Steric-inhibition model for regulation of nucleotide exchange via the Dock180 family of GEFs. Curr Biol. 2005; 15(4):371-7. DOI: 10.1016/j.cub.2005.01.050. View

Tunyasuvunakool K, Adler J, Wu Z, Green T, Zielinski M, Zidek A . Highly accurate protein structure prediction for the human proteome. Nature. 2021; 596(7873):590-596. PMC: 8387240. DOI: 10.1038/s41586-021-03828-1. View

Abu-Thuraia A, Gauthier R, Chidiac R, Fukui Y, Screaton R, Gratton J . Axl phosphorylates Elmo scaffold proteins to promote Rac activation and cell invasion. Mol Cell Biol. 2014; 35(1):76-87. PMC: 4295393. DOI: 10.1128/MCB.00764-14. View

Lu M, Ravichandran K . Dock180-ELMO cooperation in Rac activation. Methods Enzymol. 2006; 406:388-402. DOI: 10.1016/S0076-6879(06)06028-9. View

Sakurai T, Kukimoto-Niino M, Kunimura K, Yamane N, Sakata D, Aihara R . A conserved PI(4,5)P2-binding domain is critical for immune regulatory function of DOCK8. Life Sci Alliance. 2021; 4(4). PMC: 7893821. DOI: 10.26508/lsa.202000873. View

Cote J, Vuori K . Identification of an evolutionarily conserved superfamily of DOCK180-related proteins with guanine nucleotide exchange activity. J Cell Sci. 2002; 115(Pt 24):4901-13. DOI: 10.1242/jcs.00219. View

Reddien P, Horvitz H . CED-2/CrkII and CED-10/Rac control phagocytosis and cell migration in Caenorhabditis elegans. Nat Cell Biol. 2000; 2(3):131-6. DOI: 10.1038/35004000. View

Yang J, Zhang Z, Roe S, Marshall C, Barford D . Activation of Rho GTPases by DOCK exchange factors is mediated by a nucleotide sensor. Science. 2009; 325(5946):1398-402. DOI: 10.1126/science.1174468. View

Nolan K, Barrett K, Lu Y, Hu K, Vincent S, Settleman J . Myoblast city, the Drosophila homolog of DOCK180/CED-5, is required in a Rac signaling pathway utilized for multiple developmental processes. Genes Dev. 1998; 12(21):3337-42. PMC: 317223. DOI: 10.1101/gad.12.21.3337. View

10.

Harada Y, Tanaka Y, Terasawa M, Pieczyk M, Habiro K, Katakai T . DOCK8 is a Cdc42 activator critical for interstitial dendritic cell migration during immune responses. Blood. 2012; 119(19):4451-61. PMC: 3418773. DOI: 10.1182/blood-2012-01-407098. View

11.

Namkoong H, Edahiro R, Takano T, Nishihara H, Shirai Y, Sonehara K . DOCK2 is involved in the host genetics and biology of severe COVID-19. Nature. 2022; 609(7928):754-760. PMC: 9492544. DOI: 10.1038/s41586-022-05163-5. View

12.

Vetter I, Wittinghofer A . The guanine nucleotide-binding switch in three dimensions. Science. 2001; 294(5545):1299-304. DOI: 10.1126/science.1062023. View

13.

Heasman S, Ridley A . Mammalian Rho GTPases: new insights into their functions from in vivo studies. Nat Rev Mol Cell Biol. 2008; 9(9):690-701. DOI: 10.1038/nrm2476. View

14.

Ruiz-Lafuente N, Alcaraz-Garcia M, Garcia-Serna A, Sebastian-Ruiz S, Moya-Quiles M, Garcia-Alonso A . Dock10, a Cdc42 and Rac1 GEF, induces loss of elongation, filopodia, and ruffles in cervical cancer epithelial HeLa cells. Biol Open. 2015; 4(5):627-35. PMC: 4434814. DOI: 10.1242/bio.20149050. View

15.

Kunisaki Y, Nishikimi A, Tanaka Y, Takii R, Noda M, Inayoshi A . DOCK2 is a Rac activator that regulates motility and polarity during neutrophil chemotaxis. J Cell Biol. 2006; 174(5):647-52. PMC: 2064308. DOI: 10.1083/jcb.200602142. View

16.

Mallery E, Yanagisawa M, Zhang C, Lee Y, Robles L, Alonso J . Tandem C2 domains mediate dynamic organelle targeting of a DOCK family guanine nucleotide exchange factor. J Cell Sci. 2022; 135(7). DOI: 10.1242/jcs.259825. View

17.

Weng Z, Situ C, Lin L, Wu Z, Zhu J, Zhang R . Structure of BAI1/ELMO2 complex reveals an action mechanism of adhesion GPCRs via ELMO family scaffolds. Nat Commun. 2019; 10(1):51. PMC: 6318265. DOI: 10.1038/s41467-018-07938-9. View

18.

Meller N, Merlot S, Guda C . CZH proteins: a new family of Rho-GEFs. J Cell Sci. 2005; 118(Pt 21):4937-46. DOI: 10.1242/jcs.02671. View

19.

Balagopalan L, Chen M, Geisbrecht E, Abmayr S . The CDM superfamily protein MBC directs myoblast fusion through a mechanism that requires phosphatidylinositol 3,4,5-triphosphate binding but is independent of direct interaction with DCrk. Mol Cell Biol. 2006; 26(24):9442-55. PMC: 1698515. DOI: 10.1128/MCB.00016-06. View

20.

Buchwald G, Friebel A, Galan J, Hardt W, Wittinghofer A, Scheffzek K . Structural basis for the reversible activation of a Rho protein by the bacterial toxin SopE. EMBO J. 2002; 21(13):3286-95. PMC: 126081. DOI: 10.1093/emboj/cdf329. View