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PDBsum entry 2m2f
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Hydrolase regulator
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PDB id
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2m2f
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References listed in PDB file
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Key reference
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Title
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Membrane-Proximal domain of a disintegrin and metalloprotease-17 represents the putative molecular switch of its shedding activity operated by protein-Disulfide isomerase.
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Authors
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S.Düsterhöft,
S.Jung,
C.W.Hung,
A.Tholey,
F.D.Sönnichsen,
J.Grötzinger,
I.Lorenzen.
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Ref.
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J Am Chem Soc, 2013,
135,
5776-5781.
[DOI no: ]
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PubMed id
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Abstract
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A disintegrin and metalloprotease-17 (ADAM17) is a major sheddase responsible
for the regulation of a wide range of biological processes, like cellular
differentiation, regeneration, or cancer progression. Hitherto, the mechanism
regulating the enzymatic activity of ADAM17 is poorly understood. Recently,
protein-disulfide isomerase (PDI) was shown to interact with ADAM17 and to
down-regulate its enzymatic activity. Here we demonstrate by NMR spectroscopy
and tandem-mass spectrometry that PDI directly interacts with the
membrane-proximal domain (MPD), a domain of ADAM17 involved in its dimerization
and substrate recognition. PDI catalyzes an isomerization of disulfide bridges
within the thioredoxin motif C600XXC603 of the MPD and results in a drastic
structural change between an active open state and an inactive closed
conformation. This conformational change of the MPD putatively acts as a
molecular switch, facilitating a global reorientation of the extracellular
domains in ADAM17 and regulating its shedding activity.
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