Implications of the picornavirus capsid structure for polyprotein processing.

Abstract

Mature picornaviral proteins are derived by progressive, posttranslational cleavage of a precursor polyprotein. These cleavages play a role in the control of virus functions. Although the processed termini are separated by as much as 75 A in the native virus capsid, the fold and arrangement of polypeptide chains in a protomer before proteolysis are likely to be similar to that found in the mature virus. The three-dimensional structures of rhinovirus and Mengo virus suggest that the cleavage sites within the protomeric precursor are in structurally flexible regions. The final proteolytic processing event, maturation of the virion peptide VPO (also called peptide 1AB) appears to occur by an unusual autocatalytic serine protease-type mechanism possibly involving viral RNA basic groups that would serve as protonabstractors during the cleavage reaction.Controlled limited proteolysis plays a major role in the regulation of many biological processes. Examples are activation of zymogens to enzymes and prohormones to hormones, assembly of cytoskeletal components, control of cellular differentiation, initiation of cascade mechanisms such as blood clotting, removal of signal peptides in the transport of proteins across membranes, and the recycling of cellular proteins. In a viral life cycle, proteolysis can be involved in the differential control of host versus viral biosynthesis, in posttranslational modification of a precursor polyprotein, and in directing assembly events. Most of these processes utilize one of four different types of enzymic activity: serine proteases, cysteine proteases, acid proteases, or metalloproteases. Both convergent and divergent evolution have been involved in producing the observed mechanisms. Here we present evidence suggesting a viral proteolytic mechanism in which both protein and nucleic acid components participate.Picornaviruses (1) are of major economic and medical importance. The family contains a diverse variety of highly virulent human and animal pathogens, which traditionally are subdivided into four genera on the basis of physical properties of the virions. The subgroups include rhinoviruses (human and bovine), cardioviruses [e.g., Mengo, encephalomyocarditis (EMC) and Theiler viruses], enteroviruses (e.g., polio, hepatitis A, and coxsackie viruses), and aphthoviruses (foot-and-mouth disease viruses). In spite of the disparate afflictions caused by these agents, recent determinations of three-dimensional structures (2-4) and nucleotide sequences have shown that all picornaviruses share remarkable similarity in their particle structure and genome organization. Indeed, the similarity also extends to plant RNA viruses (2) and insect RNA viruses (J. E. Johnson, personal communication).Picornavirus virions contain a single, positive-stranded RNA genome (of between 7000 and 8500 bases) enclosed in a protein capsid shell with an external diameter of around 300 A. The capsids are composed of 60 copies of four nonidentical virion polypeptide chains (VP1, VP2, VP3, and VP4). The RNA c...

Cleavage site analysis in picornaviral polyproteins: Discovering cellular targets by neural networks

“…I). Concomitantly with RNA encapsidation, VPO is cleaved to VP4 and VP2; it is believed that the RNA itself exerts a catalytic function in this event (Arnold et a!., 1987;Harber et al, 1991;Bishop &Anderson, 1993;Basavappa et al, 1994).…”

“…I). Concomitantly with RNA encapsidation, VPO is cleaved to VP4 and VP2; it is believed that the RNA itself exerts a catalytic function in this event (Arnold et a!., 1987;Harber et al, 1991;Bishop &Anderson, 1993;Basavappa et al, 1994).In addition to processing of the viral polyprotein, the proteinases also cleave cellular targets. When infected with poliovirus, at least nine acidic and five basic cellular proteins were shown to be degraded in two-dimensional gel electrophoresis (Urzanqui & Carrasco, 1989).…”

Conserved sequence features of inteins (protein introns) and their use in identifying new inteins and related proteins

“…For example, the final proteolytic cleavage of the picornaviruses polyprotein is apparently autocatalytic (Arnold et al, 1987) and some of the recently discovered prokaryotic polyproteins contain spacer regions that are removed in the polyprotein maturation (ThonyMeyer et al, 1992). The posttranslational cleavage of viral polyproteins occurs by a number of different processes involving autocatalysis and different types of viral and cellular proteases.…”

Viral cell recognition and entry

“…Five VP3 amino termini form a 5-stranded Abraham & Colonno, 1984;Greve et al, 1989;Staunton et al, 1989 Abraham & Colonno, 1984;Hofer et al, 1994Mendelsohn et al, 1989Colonno et al, 1986Roivainen et al, 1991Colonno et al, 1986Roivainen et al, 1991;Schultz & Crowell, 1983Lonberg-Holm et al, 1976Bergelson et al, 1992Crowell, 1966Sekiguchi et al, 1982Mason et al, 1993Burness, 1981Burness & Pardoe, 1983 helical &cylinder on the virion's interior about each icosahedral 5-fold axis. This &cylinder stabilizes the pentamer and is thought to be important for its assembly (Hogle et al, 1985;Arnold et al, 1987).…”