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PDBsum entry 4zri
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Signaling protein/transferase
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PDB id
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4zri
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References listed in PDB file
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Key reference
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Title
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Angiomotin binding-Induced activation of merlin/nf2 in the hippo pathway.
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Authors
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Y.Li,
H.Zhou,
F.Li,
S.W.Chan,
Z.Lin,
Z.Wei,
Z.Yang,
F.Guo,
C.J.Lim,
W.Xing,
Y.Shen,
W.Hong,
J.Long,
M.Zhang.
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Ref.
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Cell Res, 2015,
25,
801-817.
[DOI no: ]
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PubMed id
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Abstract
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The tumor suppressor Merlin/NF2 functions upstream of the core Hippo pathway
kinases Lats1/2 and Mst1/2, as well as the nuclear E3 ubiquitin ligase
CRL4(DCAF1). Numerous mutations of Merlin have been identified in
Neurofibromatosis type 2 and other cancer patients. Despite more than two
decades of research, the upstream regulator of Merlin in the Hippo pathway
remains unknown. Here we show by high-resolution crystal structures that the
Lats1/2-binding site on the Merlin FERM domain is physically blocked by Merlin's
auto-inhibitory tail. Angiomotin binding releases the auto-inhibition and
promotes Merlin's binding to Lats1/2. Phosphorylation of Ser518 outside the
Merlin's auto-inhibitory tail does not obviously alter Merlin's conformation,
but instead prevents angiomotin from binding and thus inhibits Hippo pathway
kinase activation. Cancer-causing mutations clustered in the angiomotin-binding
domain impair angiomotin-mediated Merlin activation. Our findings reveal that
angiomotin and Merlin respectively interface cortical actin filaments and core
kinases in Hippo signaling, and allow construction of a complete Hippo signaling
pathway.
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