Foot-and-mouth disease virus leader proteinase: Structural insights into the mechanism of intermolecular cleavage

Author(s)

Steinberger, Jutta ^[1] ; Grishkovskaya, Irina ^[2] ; Cencic, Regina ^[1] ; Juliano, Luiz ^[3] ; Juliano, Maria A. ^[3] ; Skern, Tim ^[1]

Affiliation

^[1] Med Univ Vienna, Max F Perutz Labs, A-1030 Vienna - Austria

^[2] Univ Vienna, Dept Struct & Computat Biol, Max F Perutz Labs, A-1030 Vienna - Austria

^[3] Univ Fed Sao Paulo, Escola Paulista Med, Dept Biophys, BR-0404420 Sao Paulo - Brazil

• Document type: Journal article
• Source: VIROLOGY; v. 468, p. 397-408, NOV 2014.
• Web of Science Citations: 10

Abstract

Translation of foot-and-mouth disease virus RNA initiates at one of two start codons leading to the synthesis of two forms of leader proteinase L(pr)o (Lab(pro) and Lb(pro)). These forms free themselves from the viral polyprotein by intra- and intermolecular self-processing and subsequently cleave the cellular eukaryotic initiation factor (eIF) 4G. During infection, Lb(pro) removes six residues from its own C-terminus, generating sLb(pro). We present the structure of sLb(pro) bound to the inhibitor E64-R-P-NH2, illustrating how sLb(pro) can cleave between Lys/Gly and Gly/Arg pairs. In intermolecular cleavage on polyprotein substrates, Lb(pro) was unaffected by P1 or P1' substitutions and processed a substrate containing nine eIF4GI cleavage site residues whereas sLb(pro) failed to cleave the eIF4GI containing substrate and cleaved appreciably more slowly on mutated substrates. Introduction of 70 eIF4GI residues bearing the Lb(pro) binding site restored cleavage. These data imply that Lb(pro) and sLb(pro) may have different functions in infected cells. (C) 2014 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/3.0/). (AU)

• FAPESP's process: 12/50191-4 - Synthesis, kinetic studies and applications of substrates and inhibitors for proteolytic enzymes
• Grantee: Maria Aparecida Juliano
• Support Opportunities: Research Projects - Thematic Grants