Structure of the foot-and-mouth disease virus leader protease: a papain-like fold adapted for self-processing and eIF4G recognition

Area of Science:

• Virology
• Structural Biology
• Molecular Biology

Background:

• Foot-and-mouth disease virus (FMDV) leader protease is essential for viral replication.
• This protease inhibits host cell protein synthesis by cleaving eukaryotic initiation factor 4G (eIF4G).

Purpose of the Study:

• To elucidate the structural basis of FMDV leader protease function.
• To understand how the protease recognizes and cleaves distinct viral and cellular substrates.

Main Methods:

• X-ray crystallography was used to determine the 3D structure of the FMDV leader protease.
• Structural analysis focused on the catalytic domain, C-terminal extension, and active site features.

Main Results:

• The crystal structure reveals a papain-like cysteine protease fold with a flexible C-terminal extension.
• The extension appears to mediate intramolecular self-processing, while distinct active site features recognize different cleavage sequences (viral polyprotein and eIF4G).
• The active site groove is narrow and negatively charged, contributing to substrate specificity.

Conclusions:

• The FMDV leader protease structure demonstrates adaptation of the papain fold for viral needs, with a minimal core domain and modified active site.
• Specific surface features facilitate self-processing from the viral polyprotein.
• Understanding this structure provides insights into viral pathogenesis and potential therapeutic targets.