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PDBsum entry 2pr9
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References listed in PDB file
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Key reference
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Title
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Regulation of synaptic inhibition by phospho-Dependent binding of the ap2 complex to a yecl motif in the gabaa receptor gamma2 subunit.
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Authors
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J.T.Kittler,
G.Chen,
V.Kukhtina,
A.Vahedi-Faridi,
Z.Gu,
V.Tretter,
K.R.Smith,
K.Mcainsh,
I.L.Arancibia-Carcamo,
W.Saenger,
V.Haucke,
Z.Yan,
S.J.Moss.
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Ref.
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Proc Natl Acad Sci U S A, 2008,
105,
3616-3621.
[DOI no: ]
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PubMed id
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Abstract
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The regulation of the number of gamma2-subunit-containing GABA(A) receptors
(GABA(A)Rs) present at synapses is critical for correct synaptic inhibition and
animal behavior. This regulation occurs, in part, by the controlled removal of
receptors from the membrane in clathrin-coated vesicles, but it remains unclear
how clathrin recruitment to surface gamma2-subunit-containing GABA(A)Rs is
regulated. Here, we identify a gamma2-subunit-specific Yxxvarphi-type-binding
motif for the clathrin adaptor protein, AP2, which is located within a site for
gamma2-subunit tyrosine phosphorylation. Blocking GABA(A)R-AP2 interactions via
this motif increases synaptic responses within minutes. Crystallographic and
biochemical studies reveal that phosphorylation of the Yxxvarphi motif inhibits
AP2 binding, leading to increased surface receptor number. In addition, the
crystal structure provides an explanation for the high affinity of this motif
for AP2 and suggests that gamma2-subunit-containing heteromeric GABA(A)Rs may be
internalized as dimers or multimers. These data define a mechanism for tyrosine
kinase regulation of GABA(A)R surface levels and synaptic inhibition.
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Figure 3.
Crystal structure of the GABA[A]R γ2-subunit YECL-pep
complexed with μ2–AP2 (157–435). (A) Ribbon diagram showing
the binding site within the signal-binding domain of μ2–AP2
complexed with a peptide corresponding to GABA[A]R γ2-subunit
residues 362–371 (gold). (B) Surface representation of the γ2
peptide-binding interface with μ2–AP2, including an overlay
with the endocytic motif of EGFR (turquoise) to compare binding
of the two motifs.
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Figure 4.
Structure of the crystallographic dimer complexed with
YECL-pep. (A) Structure of the crystallographic dimer showing
the elongated banana-shaped binding pocket of a single
YGYECL-pep on the μ2–AP2 dimer surface with the second
peptide shown in surface representation. (B) Close-up view to
show direct molecular interactions between the γ2-subunit
YECL-pep and the other monomer in the crystallographic dimer.
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