The effects of the codon usage and translation speed on protein folding of 3Dpol of foot-and-mouth disease virus

Abstract

Foot-and-mouth disease virus (FMDV) can cause a highly infectious disease of cloven-hoofed livestock including sheep, domestic pig and cattle. As for the sever economic and social effects of a foot-and-mouth disease (FMD) outbreak, FMD has been recognized as the most important constraint to international trade in animals and animal products by the World Organization for Animal Heath (OIE) (Leforban 1999). FMDV is one of the members in the Aphthovirus genus which is classified into the Picornaviridae family. This virus exists in the form of seven different serotypes: Asia 1, O, C, A and South African Territories 1 (SAT 1), SAT 2 and SAT 3, but a many subtypes have evolved within each serotype. The genome of FMDV consists of a single open reading frame (ORF) flanked by a 5′ untranslated region and a 3′untranslated region. The ORF encodes 12 viral proteins, from 5′ termination to 3′ termination, including the leader protease (L), four capsid proteins (VP4, VP2, VP3 and VP1) and the nonstructural proteins 2A, 2B, 2C, 3A, 3B, 3C and 3D (Cooke and Westover 2008; Klein 2009). In Picornaviridae family, the 3D, namely RNAdependent RNA polymerase, is responsible for synthesis of RNA virus genomes. Under physiological conditions, 3D catalyze the formation of phosphodiester bonds between ribonucleotides in an RNA template-dependent fashion. However, because of the limited template copying fidelity of 3D, FMDV genome replication reflects the error-prone nature(Pariente et al. 2003). Given the important function of 3D for virus multiplication, the FMDV 3D has been the subject of intensive study for a long time. The 3D was first described in polymerase complex in the infected cells by FMDV. This complex was originally called the virus infection-associated antigen (VIAA), since it could be recognized by positive serum against FMDV (Cowan and Graves 1966). Subsequently, this VIAA was identified to contain the 3D (Lowe and Brown 1981; Newman et al. 1979; Robertson et al. 1983). Among the different FMDV serotypes or subtypes, the amino acid sequence for 3D of FMDV are conserved to some degree (Martinez-Salas et al. 1985; Villaverde et al. 1988), furthermore, some variable residues, invariable residues and peptide motifs were thought to play important roles in sustaining the functional integrity of the 3D (Carrillo et al. 2005; Doherty et al. 1999; George et al. 2001; Kaku et al. 1999; Xiang et al. 1998). However, these observations fail to indicate the overall structure of FMDV 3D. Fortunately, at this time, crystallization structure of FMDV 3D has been identified and the structure-function relationships were analyzed. The two studies help researchers to understand FMDV genome synthesis at the molecular level, account for the error-prone properties of the replication machinery (Ferrer-Orta et al. 2004, 2009). The primary sequence was regarded as the determinant of the protein secondary structure, hence, some studies of various protein structures were carried out based on this theory (Chou and Fasman 1974, 1978; Lim 1974; Qian and Sejnowski 1988; Xiao-xia Ma and Yu-ping Feng contributed equally to this work.