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PDBsum entry 2n8t
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Ligase/peptide
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PDB id
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2n8t
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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 studies of the nedd4 ww domains and their selectivity for the connexin43 (cx43) carboxyl terminus.
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Authors
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G.Spagnol,
F.Kieken,
J.L.Kopanic,
H.Li,
S.Zach,
K.L.Stauch,
R.Grosely,
P.L.Sorgen.
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Ref.
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J Biol Chem, 2016,
291,
7637-7650.
[DOI no: ]
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PubMed id
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Abstract
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Neuronal precursor cell-expressed developmentally down-regulated 4 (Nedd4) was
the first ubiquitin protein ligase identified to interact with connexin43
(Cx43), and its suppressed expression results in accumulation of gap junction
plaques at the plasma membrane. Nedd4-mediated ubiquitination of Cx43 is
required to recruit Eps15 and target Cx43 to the endocytic pathway. Although the
Cx43 residues that undergo ubiquitination are still unknown, in this study we
address other unresolved questions pertaining to the molecular mechanisms
mediating the direct interaction between Nedd4 (WW1-3 domains) and Cx43
(carboxyl terminus (CT)). All three WW domains display a similar three
antiparallel β-strand structure and interact with the same
Cx43CT(283)PPXY(286)sequence. Although Tyr(286)is essential for the interaction,
MAPK phosphorylation of the preceding serine residues (Ser(P)(279)and
Ser(P)(282)) increases the binding affinity by 2-fold for the WW domains (WW2
> WW3 ≫ WW1). The structure of the WW2·Cx43CT(276-289)(Ser(P)(279),
Ser(P)(282)) complex reveals that coordination of Ser(P)(282)with the end of
β-strand 3 enables Ser(P)(279)to interact with the back face of β-strand 3
(Tyr(286)is on the front face) and loop 2, forming a horseshoe-shaped
arrangement. The close sequence identity of WW2 with WW1 and WW3 residues that
interact with the Cx43CT PPXY motif and Ser(P)(279)/Ser(P)(282)strongly suggests
that the significantly lower binding affinity of WW1 is the result of a more
rigid structure. This study presents the first structure illustrating how
phosphorylation of the Cx43CT domain helps mediate the interaction with a
molecular partner involved in gap junction regulation.
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