Analysis of the structure-activity relationship of four herpesviral UL97 subfamily protein kinases reveals partial but not full functional conservation.
Herpesviral protein kinases of the UL97 subfamily are expressed by all known herpesviruses but the degree of functional conservation is unclear. A selection of representative members was investigated by a comparative structural and functional analysis. The coding sequences of human cytomegalovirus (HCMV) pUL97, rat CMV pR97, Epstein-Barr virus BGLF4, and herpes simplex virus UL13 showed a low degree of amino acid identity. A computational approach employing fold recognition techniques revealed structural similarity to the cellular kinase Cdk2 with a high level of conservation of the functionally important residues in ATP binding sites and the catalytic centers. Analyses of in vitro activities of these herpesviral protein kinases, including measurements of phosphorylation of cellular substrates, trans-complementation experiments with a UL97-deleted HCMV mutant, and sensitivity profiles toward protein kinase inhibitors, demonstrated marked similarities between pUL97 and pR97 and to a lesser extent between pUL97 and BGLF4 or UL13. Thus, the structure-activity analysis of pUL97-like herpesviral protein kinases indicates a partial but not a full conservation of their functional properties among the herpesviruses.
Romaker
Daniel
D
Institute for Clinical and Molecular Virology, and Department of Bioinformatics, University of Erlangen-Nuremberg, Germany.
Schregel
Vera
V
Maurer
Katja
K
Auerochs
Sabrina
S
Marzi
Andrea
A
Sticht
Heinrich
H
Marschall
Manfred
M
D000255:Adenosine Triphosphate / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D020134:Catalytic Domain; D002460:Cell Line; D017124:Conserved Sequence; D003587:Cytomegalovirus / Q000201:enzymology / Q000235:genetics / Q000502:physiology; D006564:Herpesviridae / Q000201:enzymology*; D004854:Herpesvirus 4, Human / Q000201:enzymology; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011494:Protein Kinases / Q000737:chemistry* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry* / Q000378:metabolism; D051381:Rats; D013329:Structure-Activity Relationship; D014764:Viral Proteins / Q000737:chemistry* / Q000378:metabolism; D014779:Virus Replication
D047428:Protein Kinase Inhibitors; D014764:Viral Proteins; D000255:Adenosine Triphosphate; D011494:Protein Kinases; C406063:BGLF4 protein, Epstein-Barr virus; D017853:Phosphotransferases (Alcohol Group Acceptor); C082380:UL13 protein, Simplexvirus; C075365:ganciclovir kinase; D017346:Protein Serine-Threonine Kinases