title: Amino acid preferences for a critical substrate binding subsite of retroviral proteases in type 1 cleavage sites.
abstract: The specificities of the proteases of 11 retroviruses representing each of the seven genera of the family Retroviridae were studied using a series of oligopeptides with amino acid substitutions in the P2 position of a naturally occurring type 1 cleavage site (Val-Ser-Gln-Asn-Tyr Pro-Ile-Val-Gln; the arrow indicates the site of cleavage) in human immunodeficiency virus type 1 (HIV-1). This position was previously found to be one of the most critical in determining the substrate specificity differences of retroviral proteases. Specificities at this position were compared for HIV-1, HIV-2, equine infectious anemia virus, avian myeloblastosis virus, Mason-Pfizer monkey virus, mouse mammary tumor virus, Moloney murine leukemia virus, human T-cell leukemia virus type 1, bovine leukemia virus, human foamy virus, and walleye dermal sarcoma virus proteases. Three types of P2 preferences were observed: a subgroup of proteases preferred small hydrophobic side chains (Ala and Cys), and another subgroup preferred large hydrophobic residues (Ile and Leu), while the protease of HIV-1 preferred an Asn residue. The specificity distinctions among the proteases correlated well with the phylogenetic tree of retroviruses prepared solely based on the protease sequences. Molecular models for all of the proteases studied were built, and they were used to interpret the results. While size complementarities appear to be the main specificity-determining features of the S2 subsite of retroviral proteases, electrostatic contributions may play a role only in the case of HIV proteases. In most cases the P2 residues of naturally occurring type 1 cleavage site sequences of the studied proteases agreed well with the observed P2 preferences.
authors.affiliation: Department of Biochemistry and Molecular Biology, Research Center for Molecular Medicine, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary.
authors.forename: Péter
authors.initials: P
authors.lastname: Bagossi
authors.forename: Tamás
authors.initials: T
authors.lastname: Sperka
authors.forename: Anita
authors.initials: A
authors.lastname: Fehér
authors.forename: János
authors.initials: J
authors.lastname: Kádas
authors.forename: Gábor
authors.initials: G
authors.lastname: Zahuczky
authors.forename: Gabriella
authors.initials: G
authors.lastname: Miklóssy
authors.forename: Péter
authors.initials: P
authors.lastname: Boross
authors.forename: József
authors.initials: J
authors.lastname: Tözsér
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D009189:Avian Myeloblastosis Virus / Q000201:enzymology; D001665:Binding Sites; D017124:Conserved Sequence; D030283:Epsilonretrovirus / Q000201:enzymology; D015497:HIV-1 / Q000201:enzymology; D015498:HIV-2 / Q000201:enzymology; D015368:Human T-lymphotropic virus 1 / Q000201:enzymology; D057927:Hydrophobic and Hydrophilic Interactions; D004860:Infectious Anemia Virus, Equine / Q000201:enzymology; D001909:Leukemia Virus, Bovine / Q000201:enzymology; D008324:Mammary Tumor Virus, Mouse / Q000201:enzymology; D016093:Mason-Pfizer monkey virus / Q000201:enzymology; D008969:Molecular Sequence Data; D008979:Moloney murine leukemia virus / Q000201:enzymology; D009842:Oligopeptides / Q000378:metabolism*; D010447:Peptide Hydrolases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010802:Phylogeny; D012190:Retroviridae / Q000201:enzymology*; D016415:Sequence Alignment; D016092:Spumavirus / Q000201:enzymology; D055672:Static Electricity; D013379:Substrate Specificity
chemical_list: D009842:Oligopeptides; D010447:Peptide Hydrolases