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Crystal structures of VAP1 reveal ADAMs' MDC domain architecture and its unique C‐shaped scaffold
Open accessAbstract
ADAMs (a disintegrin and metalloproteinase) are sheddases possessing extracellular metalloproteinase/disintegrin/cysteine-rich (MDC) domains. ADAMs uniquely display both proteolytic and adhesive activities on the cell surface, however, most of their physiological targets and adhesion mechanisms remain unclear. Here for the first time, we reveal the ADAMs' MDC architecture and a potential target-binding site by solving crystal structures of VAP1, a snake venom homolog of mammalian ADAMs. The D-domain protrudes from the M-domain opposing the catalytic site and constituting a C-shaped arm with cores of Ca2+ ions. The disintegrin-loop, supposed to interact with integrins, is packed by the C-domain and inaccessible for protein binding. Instead, the hyper-variable region (HVR) in the C-domain, which has a novel fold stabilized by the strictly conserved disulfide bridges, constitutes a potential protein-protein adhesive interface. The HVR is located at the distal end of the arm and faces toward the catalytic site. The C-shaped structure implies interplay between the ADAMs' proteolytic and adhesive domains and suggests a molecular mechanism for ADAMs' target recognition for shedding.
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“Based on the model, known mutations that cause disease (magenta spheres in Fig. 3A) could act by hindering catalysis (R26K, R32Q, and L50P, near active site) or produce steric clashes (G154R) (19) in the hydrophobic core.”
From Accurate prediction of protein structures and interactions using a 3-track network (2021) · cites this paper as [19]
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Cited by
Sorted by citations
Accurate prediction of protein structures and interactions using a 3-track network
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“The ADAMs contain prodomain and metalloprotease domains; the fold of the metalloprotease is known (18, 19), but not that of the prodomain, which has no homologs of known structure.”
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“Crystallographic studies of a portion of native ADAM10 and the related vascular apoptosis-inducing protein-1 reveal a highly conserved, multidomain C-shaped structure containing 17 disulfide bonds and several calcium-binding sites (25, 26).”
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Metadata
- Authors
- Takeda, S., Igarashi, T., Mori, H., & Araki, S.
- Affiliations
- SPring-8 (JP)
- National Cerebral and Cardiovascular Center (JP)
- Nagoya University (JP)
- Corresponding author
- Takeda, Soichi
- ORCID
- Takeda, Soichi
- Venue
- The EMBO Journal
- Published
- 2006-05-11
- Volume
- 25
- Issue
- 11
- Pages
- 2388-2396
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC1478178
- OpenAlex
- W2000001290
- Cited by
- 202
- References
- 45
- Citations by year
- 2025: 10 · 2024: 4 · 2023: 4 · 2022: 4 · 2021: 9 · 2020: 4 · 2019: 5 · 2018: 2 · 2017: 11 · 2016: 12 · 2015: 7 · 2014: 14 · 2013: 9 · 2012: 17
- FWCI
- 8.36
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The EMBO Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Takeda Science Foundation
- Senri Life Science Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Enzyme Structure and Function
- Health Sciences › Medicine › Hematology › Blood Coagulation and Thrombosis Mechanisms
- Keywords
- ADAMS, snake venom proteins, disintegrins, metalloproteinases, hypervariable region, disulfide bonds, calcium ions, extracellular matrix, crystal structure
- MeSH terms
- Amino Acid Sequence, Animals, Crotalid Venoms, Humans, Metalloendopeptidases, Models, Molecular, Molecular Sequence Data, Sequence Alignment, Protein Structure, Tertiary, Crystallography, X-Ray, Apoptosis Regulatory Proteins, ADAM Proteins
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