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PDBsum entry 3vgo
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References listed in PDB file
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Key reference
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Title
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Autoinhibition and phosphorylation-Induced activation mechanisms of human cancer and autoimmune disease-Related e3 protein cbl-B.
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Authors
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Y.Kobashigawa,
A.Tomitaka,
H.Kumeta,
N.N.Noda,
M.Yamaguchi,
F.Inagaki.
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Ref.
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Proc Natl Acad Sci U S A, 2011,
108,
20579-20584.
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PubMed id
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Abstract
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Cbl-b is a RING-type E3 ubiquitin ligase that functions as a negative regulator
of T-cell activation and growth factor receptor and nonreceptor-type tyrosine
kinase signaling. Cbl-b dysfunction is related to autoimmune diseases and
cancers in humans. However, the molecular mechanism regulating its E3 activity
is largely unknown. NMR and small-angle X-ray scattering analyses revealed that
the unphosphorylated N-terminal region of Cbl-b forms a compact structure by an
intramolecular interaction, which masks the interaction surface of the RING
domain with an E2 ubiquitin-conjugating enzyme. Phosphorylation of Y363, located
in the helix-linker region between the tyrosine kinase binding and the RING
domains, disrupts the interdomain interaction to expose the E2 binding surface
of the RING domain. Structural analysis revealed that the phosphorylated
helix-RING region forms a compact structure in solution. Moreover, the phosphate
group of pY363 is located in the vicinity of the interaction surface with UbcH5B
to increase affinity by reducing their electrostatic repulsion. Thus, the
phosphorylation of Y363 regulates the E3 activity of Cbl-b by two mechanisms:
one is to remove the masking of the RING domain from the tyrosine kinase binding
domain and the other is to form a surface to enhance binding affinity to E2.
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