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PDBsum entry 2oo9
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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 for uba-Mediated dimerization of c-Cbl ubiquitin ligase.
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Authors
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G.Kozlov,
P.Peschard,
B.Zimmerman,
T.Lin,
T.Moldoveanu,
N.Mansur-Azzam,
K.Gehring,
M.Park.
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Ref.
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J Biol Chem, 2007,
282,
27547-27555.
[DOI no: ]
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PubMed id
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Abstract
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Ligand-induced down-regulation by the ubiquitin-protein ligases, c-Cbl and
Cbl-b, controls signaling downstream from many receptor-tyrosine kinases (RTK).
Cbl proteins bind to phosphotyrosine residues on activated RTKs to affect
ligand-dependent ubiquitylation of these receptors targeting them for
degradation in the lysosome. Both c-Cbl and Cbl-b contain a ubiquitin-associated
(UBA) domain, which is important for Cbl dimerization and tyrosine
phosphorylation; however, the mechanism of UBA-mediated dimerization and its
requirement for Cbl biological activity is unclear. Here, we report the crystal
structure of the UBA domain of c-Cbl refined to 2.1-A resolution. The structure
reveals the protein is a symmetric dimer tightly packed along a large
hydrophobic surface formed by helices 2 and 3. NMR chemical shift mapping
reveals heterodimerization can occur with the related Cbl-b UBA domain via the
same surface employed for homodimerization. Disruption of c-Cbl dimerization by
site-directed mutagenesis impairs c-Cbl phosphorylation following activation of
the Met/hepatocyte growth factor RTK and c-Cbl-dependent ubiquitination of Met.
This provides direct evidence for a role of Cbl dimerization in terminating
signaling following activation of RTKs.
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Figure 3.
Structure of the UBA domain from c-Cbl.A, ribbon
representation of the UBA dimer. One protomer is shown in
magenta, another is in yellow. Helices are labeled as α1-α3 in
one protomer and α1′-α3′ in another protomer. B,
hydrophobic core of the c-Cbl UBA domain. Respective residues
are shown as sticks and labeled. C, the enlarged view of the
hydrophobic dimer interface. Key residues in the dimer are shown
as sticks and labeled. D, intermolecular hydrogen bonds (dotted
line) involving Lys^876 and Glu^894 from both c-Cbl UBA
protomers.
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Figure 6.
Comparison of protomer arrangement in the structures of (A)
c-Cbl UBA domain, (B) Cbl-b UBA domain (PDB code 2OOA), and (C)
dimerization domain of doublesex protein (PDB code 1ZV1). Color
changes from NH[2] terminus (blue) to COOH terminus (red).
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2007,
282,
27547-27555)
copyright 2007.
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