3L4C

Structural basis of membrane-targeting by Dock180

Summary for 3L4C

• Entry DOI: 10.2210/pdb3l4c/pdb
• Descriptor: Dedicator of cytokinesis protein 1, BETA-MERCAPTOETHANOL (3 entities in total)
• Functional Keywords: dock180, dock1, phosphoinositide specificity, guanine exchange factor, rho gtpase, cytoskeleton, cell migration, cell polarity, apoptosis, cytoplasm, guanine-nucleotide releasing factor, membrane, phagocytosis, phosphoprotein, sh3 domain, sh3-binding, cell adhesion, cell invasion
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm : Q14185
• Total number of polymer chains: 2
• Total formula weight: 49499.81

Authors

Premkumar, L.,Bobkov, A.A.,Patel, M.,Jaroszewski, L.,Bankston, L.A.,Stec, B.,Vuori, K.,Cote, J.-F.,Liddington, R.C. (deposition date: 2009-12-18, release date: 2010-02-23, Last modification date: 2023-09-06)

Primary citation

Premkumar, L.,Bobkov, A.A.,Patel, M.,Jaroszewski, L.,Bankston, L.A.,Stec, B.,Vuori, K.,Cote, J.F.,Liddington, R.C.
Structural basis of membrane targeting by the Dock180 family of Rho family guanine exchange factors (Rho-GEFs).
J.Biol.Chem., 285:13211-13222, 2010

PubMed Abstract: The Dock180 family of atypical Rho family guanine nucleotide exchange factors (Rho-GEFs) regulate a variety of processes involving cellular or subcellular polarization, including cell migration and phagocytosis. Each contains a Dock homology region-1 (DHR-1) domain that is required to localize its GEF activity to a specific membrane compartment where levels of phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)P(3)) are up-regulated by the local activity of PtdIns 3-kinase. Here we define the structural and energetic bases of phosphoinositide specificity by the DHR-1 domain of Dock1 (a GEF for Rac1), and show that DHR-1 utilizes a C2 domain scaffold and surface loops to create a basic pocket on its upper surface for recognition of the PtdIns(3,4,5)P(3) head group. The pocket has many of the characteristics of those observed in pleckstrin homology domains. We show that point mutations in the pocket that abolish phospholipid binding in vitro ablate the ability of Dock1 to induce cell polarization, and propose a model that brings together recent mechanistic and structural studies to rationalize the central role of DHR-1 in dynamic membrane targeting of the Rho-GEF activity of Dock180.

PubMed: 20167601
DOI: 10.1074/jbc.M110.102517

Experimental method

X-RAY DIFFRACTION (2.37 Å)