Crystal structures of VAP1 reveal ADAMs' MDC domain architecture and its unique C-shaped scaffold

Area of Science:

• Structural Biology
• Biochemistry
• Molecular Biology

Background:

• ADAMs (a disintegrin and metalloproteinase) are sheddases with metalloproteinase/disintegrin/cysteine-rich (MDC) domains.
• ADAMs exhibit both proteolytic and adhesive functions, but their targets and adhesion mechanisms are largely unknown.
• Understanding ADAMs' structure is crucial for elucidating their biological roles.

Purpose of the Study:

• To determine the MDC architecture of ADAMs.
• To identify potential protein-protein interaction sites.
• To elucidate the molecular mechanism of ADAMs' target recognition.

Main Methods:

• Crystal structure determination of VAP1, a snake venom homolog of mammalian ADAMs.
• Analysis of the MDC domain architecture and identification of key structural features.

Main Results:

• The crystal structure reveals a C-shaped architecture of the MDC domain, with the D-domain protruding from the M-domain.
• The disintegrin-loop is inaccessible for protein binding, suggesting it does not interact with integrins.
• A novel hyper-variable region (HVR) in the C-domain, stabilized by disulfide bridges, forms a potential protein-protein adhesive interface.

Conclusions:

• The C-shaped structure suggests interplay between ADAMs' proteolytic and adhesive domains.
• The HVR represents a novel protein-protein binding site, distinct from the integrin-binding disintegrin-loop.
• This structural insight provides a molecular mechanism for ADAMs' target recognition and shedding activity.