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Structure of the foot-and-mouth disease virus leader protease: a papain-like fold adapted for self-processing and
A Guarné1, J Tormo, R Kirchweger
1Centre d'Investigació i Desenvolupament (CSIC), Jordi Girona Salgado 18-26, E-08034 Barcelona, Spain.
Abstract:
The leader protease of foot-and-mouth disease virus, as well as cleaving itself from the nascent viral polyprotein, disables host cell protein synthesis by specific proteolysis of a cellular protein: the eukaryotic initiation factor 4G (eIF4G). The crystal structure of the leader protease presented here comprises a globular catalytic domain reminiscent of that of cysteine proteases of the papain superfamily, and a flexible C-terminal extension found intruding into the substrate-binding site of an adjacent molecule. Nevertheless, the relative disposition of this extension and the globular domain to each other supports intramolecular self-processing. The different sequences of the two substrates cleaved during viral replication, the viral polyprotein (at LysLeuLys/GlyAlaGly) and eIF4G (at AsnLeuGly/ArgThrThr), appear to be recognized by distinct features in a narrow, negatively charged groove traversing the active centre. The structure illustrates how the prototype papain fold has been adapted to the requirements of an RNA virus. Thus, the protein scaffold has been reduced to a minimum core domain, with the active site being modified to increase specificity. Furthermore, surface features have been developed which enable C-terminal self-processing from the viral polyprotein.
Insights
Foot-and-mouth disease virus leader protease cleaves itself and host eIF4G protein synthesis factor. Its crystal structure reveals adaptations for viral replication, including a modified active site for substrate specificity.
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.