Article
- The EMBO Journal (2006) 25, 2388 - 2396
- doi:10.1038/sj.emboj.7601131
Published online: 11 May 2006
Subject Categories:
Crystal structures of VAP1 reveal ADAMs' MDC domain architecture and its unique C-shaped scaffold
Soichi Takeda1,2, Tomoko Igarashi1, Hidezo Mori1 and Satohiko Araki3
- Department of Cardiac Physiology, National Cardiovascular Center Research Institute, Suita, Osaka, Japan
- Laboratory for Structural Biochemistry, Riken Harima Institute at SPring-8, Mikazuki, Sayo, Hyogo, Japan
- Sugashima Marine Biological Laboratory, Graduate School of Science, Nagoya University, Toba, Mie, Japan
Correspondence to:
Soichi Takeda, Department of Cardiac Physiology, National Cardiovascular Center Research Institute, Fujishirodai 5-7-1, Suita, Osaka, 565-8565, Japan. Tel.: +81 6 6833 5012 ext.2381; Fax: +81 6 6872 7485; E-mail: stakeda@ri.ncvc.go.jp
Received 17 February 2006; Accepted 12 April 2006
Abstract
ADAMs (adisintegrin 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.
Keywords:
- ADAM,
- MDC,
- protein–protein interaction,
- shedding,
- snake venom metalloproteinase
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