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PDBsum entry 1y8f
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Endocytosis/exocytosis,signaling protein
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PDB id
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1y8f
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References listed in PDB file
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Key reference
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Title
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Intramolecular occlusion of the diacylglycerol-Binding site in the c1 domain of munc13-1.
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Authors
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N.Shen,
O.Guryev,
J.Rizo.
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Ref.
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Biochemistry, 2005,
44,
1089-1096.
[DOI no: ]
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PubMed id
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Abstract
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Protein kinase C (PKC) isozymes and other receptors of diacylglycerol (DAG) bind
to this widespread second messenger through their C(1) domains. These
alternative DAG receptors include munc13-1, a large neuronal protein that is
crucial for DAG-dependent augmentation of neurotransmitter release. Whereas the
structures of several PKC C(1) domains have been determined and have been shown
to require little conformational changes for ligand binding, it is unclear
whether the C(1) domains from other DAG receptors contain specific structural
features with key functional significance. To gain insight into this question,
we have determined the three-dimensional structure in solution of the munc13-1
C(1) domain using NMR spectroscopy. The overall structure includes two
beta-sheets, a short C-terminal alpha-helix, and two Zn(2+)-binding sites,
resembling the structures of PKC C(1) domains. However, the munc13-1 C(1) domain
exhibits striking structural differences with the PKC C(1) domains in the
ligand-binding site. These differences result in occlusion of the binding site
of the munc13-1 C(1) domain by a conserved tryptophan side chain that in PKCs
adopts a completely different orientation. As a consequence, the munc13-1 C(1)
domain requires a considerable conformational change for ligand binding. This
structural distinction is expected to decrease the DAG affinity of munc13-1
compared to that of PKCs, and is likely to be critical for munc13-1 function. On
the basis of these results, we propose that augmentation of neurotransmitter
release may be activated at higher DAG levels than PKCs as a potential mechanism
for uncoupling augmentation of release from the multitude of other signaling
processes mediated by DAG.
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