Structure and Function of Picornavirus Proteinases

Tim Skern; Bernhard Hampölz; Alba Guarné; Ignacio Fita; Ernst Bergmann; Michael N. G. James; Jens Petersen

doi:10.1128/9781555817916.ch17

Chapter 17 : Structure and Function of Picornavirus Proteinases

Authors: Tim Skern¹, Bernhard Hampölz¹, Alba Guarné², Ignacio Fita², Ernst Bergmann³, Michael N. G. James³, Jens Petersen⁴

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Affiliations: 1: Institute of Medical Biochemistry, Vienna Bio Center, University of Vienna, Dr. Bohr-Gasse 9/3, A-1030 Vienna, Austria; 2: Centre d'Investigació i Desenvolupament (CSIC), Jordi Girona Salgado 18-26, E-08034 Barcelona, Spain.; 3: CIHR Group in Protein Structure and Function, Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2H7, Canada; 4: Astra Zeneca, R & D Molndal, S-431 83 Molndal, Sweden

Content Type: Monograph

Publication Year: 2002

Category: Viruses and Viral Pathogenesis

Book DOI: 10.1128/9781555817916

Chapter DOI: 10.1128/9781555817916.ch17

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Abstract:

This chapter summarizes the implications of three-dimensional structures on the proteolytic mechanisms, the substrate specificities, and the functions of the proteinases in infected cells. The picornaviral polyproteins can be divided into three regions, designated P1, P2, and P3. These correspond to the N-terminal capsid protein precursor (P1, containing the four capsid proteins 1A-1D), the middle of the polyprotein containing three of the nonstructural proteins (P2, the three proteins 2A-2C), and the most C-terminal segment of the polyprotein containing four nonstructural proteins (P3, proteins 3A-3D). In the cardio- and aphthoviruses, a protein known as the leader protein precedes P1. The hepato- and parechoviruses encode only a single proteolytic enzyme and are therefore proteolytically the simplest of the picornaviruses. During the replication of a picornavirus, the physiology and ultrastructure of the infected cells are drastically modified. Thus, cellular RNA and protein synthesis as well as protein trafficking are inhibited. The chapter discusses crystal structures in terms of their mechanisms of action and specificities and how the proteinases have evolved to be able to carry out their specific roles in the replication of the respective viruses. Like Streptomyces griseus protease B (SGPB) and the 3C proteinases, HRV2 2Apro comprises two subdomains, built up by β-strands as found in chymotrypsin.

Citation: Skern T, Hampölz B, Guarné A, Fita I, Bergmann E, James M, Petersen J. 2002. Structure and Function of Picornavirus Proteinases, p 199-212. In Semler B, Wimmer E (ed), Molecular Biology of Picornavirus. ASM Press, Washington, DC. doi: 10.1128/9781555817916.ch17

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Structure and Function of Picornavirus Proteinases

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FIGURE 1

Proteolytic processing in picornaviruses. Variations in primary cleavage events among six picornavirus genera. The polyproteins of the indicated viruses are shown schematically as open boxes. Primary cleavages are indicated. The different shadings of the 2A protein reflect the differences in mechanism and size in this protein. The 2A protein of hepato- and parecho-viruses has not been shown to possess proteolytic activity.

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FIGURE 1

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FIGURE 2

(A) Proteolytic processing map of poliovirus. The RNA genome of the virus is shown at the top as a black line. The positions of the IRES, the initiating AUG and stop codons, and the poly(A) tail are indicated. The polyprotein is indicated as an open box. Positions of the proteinases and their cleavage sites are indicated. 2Apro cleavages are indicated by an open arrow, 3Cpro cleavages by a closed arrow. An open circle indicates the secondary 2Apro cleavage; an asterisk indicates cleavages carried out by 3CDpro. (B) Proteolytic processing map of FMDV. The cleavages are keyed as in (A) except that the fat closed arrow depicts the site of Lpro processing. No cleavage sites for 3CDpro have been determined. Adapted from reference 8 .

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FIGURE 2

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FIGURE 3

Structural alignments of the 3C proteinases from HAV, PV1, and HRV2. Asterisks under the residue symbols of the sequence for HRV 3C indicate identical residues in all three proteins. Dots indicate that highly similar residues are in the same positions in all three proteins. The alignments are based on the structural superpositions done in Table 4 .

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FIGURE 3

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FIGURE 4

Sequence alignment based on the structures of PV1 3Cpro and HRV2 2Apro.

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FIGURE 4

Sequence alignment based on the structures of PV1 3Cpro and HRV2 2Apro.

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Tables

Structure and Function of Picornavirus Proteinases

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TABLE 1

Cellular proteins cleaved by picornaviral proteinases

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TABLE 1

Cellular proteins cleaved by picornaviral proteinases

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TABLE 2

Published structures of picornaviral proteinases

a The structure is that of the native protein unless otherwise stated.

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TABLE 2

Published structures of picornaviral proteinases

a The structure is that of the native protein unless otherwise stated.

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TABLE 3

The sequences of the cleavage sites of the 3Cpro of HAV and PV1

a Reference 11 .

b Reference 48 .

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TABLE 3

The sequences of the cleavage sites of the 3Cpro of HAV and PV1

a Reference 11 .

b Reference 48 .

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TABLE 4

Pairwise structural comparisons among 3C proteinases and SGPB a

a The upper triangular matrix gives the root main square differences for common C α atoms (Å). The PDB accession codes for the coordinate data sets used here are: PV1 3C molecule B, available from M. James; HRV2 3C, 1CQQ; HAV 3C molecule A, 1HAV; SGPB, 3SGB. The numbers in parentheses refer to the number of pairs of C α atoms in each superposition. The lower part of the matrix contains the percentages of identical residues in the overlapped pairs. The superpositions were done using Swiss PDB Viewer (http://www.expasy.ch/spdbv/) ( 37 ).

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TABLE 4

Pairwise structural comparisons among 3C proteinases and SGPB a