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Cited by 68Protein Kinase Regulation and GTPase SignalingCellular transport and secretionProtein Structure and Dynamics

Structural Basis of Membrane Targeting by the Dock180 Family of Rho Family Guanine Exchange Factors (Rho-GEFs)

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Premkumar, Lakshmanane, Bobkov, Andrey A., Patel, Manishha, Jaroszewski, Lukasz, Bankston, Laurie A., Stec, Boguslaw, Vuori, Kristiina, Côté, Jean-Francois +1 more·2010·Journal of Biological Chemistry
DOI 10.1074/jbc.m110.102517PMC PMC2857062
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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.

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Authors
Premkumar, L., Bobkov, A. A., Patel, M., Jaroszewski, L., Bankston, L. A., Stec, B., Vuori, K., Côté, J.-F., & Liddington, R. C.
Affiliations
  • Sanford Burnham Prebys Medical Discovery Institute (US)
  • Montreal Clinical Research Institute (CA)
Corresponding author
Liddington, Robert C.
ORCID
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2010-04
Volume
285
Issue
17
Pages
13211-13222
ISSN
0021-9258 (ISSN-L)
DOI
10.1074/jbc.m110.102517
PMC
PMC2857062
OpenAlex
W2054082789
Cited by
68
References
3
Citations by year
2026: 4 · 2025: 1 · 2024: 3 · 2023: 5 · 2022: 5 · 2021: 8 · 2020: 3 · 2019: 3 · 2018: 3 · 2017: 2 · 2016: 5 · 2015: 2 · 2014: 5 · 2013: 6 · 2012: 5
FWCI
2.48
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • U.S. Department of Energy
  • National Institutes of Health (5u54gm064346-10)
  • Canadian Institutes of Health Research (77591)
  • National Institute of General Medical Sciences (U54-GM064346, U54 GM06346)
  • Basic Energy Sciences
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
Keywords
DOCK180, DOCK1, RhoGEF, membrane targeting, phosphatidylinositol 3,4,5-trisphosphate, C2 domain, pleckstrin homology domain, cell polarization, Rac1, protein structure
MeSH terms
Animals, Binding Sites, Cytoskeletal Proteins, Drosophila melanogaster, Multigene Family, Humans, Models, Molecular, Structure-Activity Relationship, Protein Structure, Secondary, Protein Structure, Tertiary, Phosphatidylinositol Phosphates, Phosphatidylinositol 3-Kinases, rho GTP-Binding Proteins, rac GTP-Binding Proteins, Drosophila Proteins, Structural Homology, Protein

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