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PDBsum entry 4xib
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References listed in PDB file
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Key reference
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Title
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A tail of two sites: a bipartite mechanism for recognition of notch ligands by mind bomb e3 ligases.
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Authors
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B.J.Mcmillan,
B.Schnute,
N.Ohlenhard,
B.Zimmerman,
L.Miles,
N.Beglova,
T.Klein,
S.C.Blacklow.
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Ref.
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Mol Cell, 2015,
57,
912-924.
[DOI no: ]
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PubMed id
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Abstract
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Mind bomb (Mib) proteins are large, multi-domain E3 ligases that promote
ubiquitination of the cytoplasmic tails of Notch ligands. This ubiquitination
step marks the ligand proteins for epsin-dependent endocytosis, which is
critical for in vivo Notch receptor activation. We present here crystal
structures of the substrate recognition domains of Mib1, both in isolation and
in complex with peptides derived from Notch ligands. The structures, in
combination with biochemical, cellular, and in vivo assays, show that Mib1
contains two independent substrate recognition domains that engage two distinct
epitopes from the cytoplasmic tail of the ligand Jagged1, one in the
intracellular membrane proximal region and the other near the C terminus.
Together, these studies provide insights into the mechanism of ubiquitin
transfer by Mind bomb E3 ligases, illuminate a key event in ligand-induced
activation of Notch receptors, and identify a potential target for therapeutic
modulation of Notch signal transduction in disease.
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