PDBsum entry 2m2f

Hydrolase regulator

PDB id: 2m2f

Contents

Protein chain

62 a.a.

PDB id:

2m2f

Name:

Hydrolase regulator

Title:

The membran-proximal domain of adam17

Structure:

Disintegrin and metalloproteinase domain-containing protein 17. Chain: a. Fragment: unp residues 581-642. Synonym: adam 17, snake venom-like protease, tnf-alpha convertase, tnf-alpha-converting enzyme. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: adam17, csvp, tace. Expressed in: escherichia coli. Expression_system_taxid: 562.

NMR struc:

20 models

Authors:

S.Duesterhoeft,S.Jung,C.Hung,A.Tholey,F.D.Soennichsen,J.Groetzinger, I.Lorenzen

Key ref:

S.Düsterhöft et al. (2013). Membrane-proximal domain of a disintegrin and metalloprotease-17 represents the putative molecular switch of its shedding activity operated by protein-disulfide isomerase. J Am Chem Soc, 135, 5776-5781. PubMed id: 23521534 DOI: 10.1021/ja400340u

Date:

20-Dec-12 Release date: 10-Apr-13

Protein chain

P78536  (ADA17_HUMAN) -  Disintegrin and metalloproteinase domain-containing protein 17 from Homo sapiens

Seq: 824 a.a.

Struc: 62 a.a.

Enzyme reactions

• Enzyme class: E.C.3.4.24.86 - Adam 17 endopeptidase.
• Cofactor: Zn(2+)

DOI no: 10.1021/ja400340u

J Am Chem Soc 135:5776-5781 (2013)

PubMed id: 23521534

Membrane-proximal domain of a disintegrin and metalloprotease-17 represents the putative molecular switch of its shedding activity operated by protein-disulfide isomerase.

S.Düsterhöft, S.Jung, C.W.Hung, A.Tholey, F.D.Sönnichsen, J.Grötzinger, I.Lorenzen.

ABSTRACT

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.