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PDBsum entry 3l4c
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Cell adhesion, cell invasion, apoptosis
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PDB id
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3l4c
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References listed in PDB file
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Key reference
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Title
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Structural basis of membrane targeting by the dock180 family of rho family guanine exchange factors (rho-Gefs).
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Authors
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L.Premkumar,
A.A.Bobkov,
M.Patel,
L.Jaroszewski,
L.A.Bankston,
B.Stec,
K.Vuori,
J.F.Côté,
R.C.Liddington.
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Ref.
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J Biol Chem, 2010,
285,
13211-13222.
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PubMed id
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Abstract
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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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