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Department Affiliation: Pharmacology and Molecular Sciences
Degree: Ph.D., University of Chicago
Rank: Professor Emeritus
Telephone Number: 410-955-8680
Fax Number: 410-955-3023
E-mail address: email@example.com
School of Medicine Address: 312A Physiology Building, 725 N. Wolfe St., Baltimore, MD 21205
Herpesvirus proteins: Applying genetic, biochemical, and imaging approaches to understand function and identify potential antiviral targets
We are probing the structure and molecular interactions of herpesvirus proteins with the objective of understanding how they work during virus replication. Our long-term goal is to define key regulatory mechanisms in virus assembly and maturation, and in the process uncover new targets for antiviral-drug development. We use cytomegalovirus (CMV) as our model system. Its ~ 230 kb genome is the largest among the known herpesviruses, and this normally 'in-check' pathogen can be a major problem in people with suppressed (e.g., anticancer chemotherapy; organ transplantation) or dysfunctional (e.g., HIV-infected) immune systems. Our recent progress on the following three active projects is described in the publications listed below.
Maturational protease (CMV ORF UL80a). This novel serine protease and closely related assembly protein precursor drive early steps in the assembly of infectious virus. We are defining how their molecular mechanism is modulated during infection, how their structure influences their function, and whether their interactions and enzymatic activities constitute viable antiviral targets.
Deubiquitinylating enzyme (CMV ORF UL48). This enzymatic activity at the amino end of the largest protein encoded by all herpesvirus genomes removes ubiquitin from itself and from other as yet unidentified substrate proteins. Its function during virus replication is unknown and a major objective of this project is to determine what that is. We are developing a high-throughput assay to screen for lead compounds that inhibit its activity.
Basic phosphoprotein (CMV ORF UL32). This protein is found only in herpesviruses closely related to CMV and is tightly associated with the outer surface of the virus 'capsid shell' that encases and protects the viral DNA. It is essential for virus replication and we are testing the hypotheses that it is required to stabilize the capsid shell against internal pressure exerted by the large size of the DNA, binds to the capsid shell via its amino end, and interacts with other proteins in the virus particle via its carboxyl end.
- Casaday, R.J., Bailey, J.R., Kalb, S.R., Brignole, E.J., Loveland, A.N., Cotter, R.J., and Gibson, W. Assembly protein precursor (pUL80.5 homolog) of simian cytomegalovirus is phosphorylated at a glycogen synthase kinase 3 site and its downstream "priming" site: Phoaphorylation affects interaction of protein with itself and with major capsid protein, J. Virol. 78:13501-13511, 2004. Pub Med Reference
- Gibson, W. Assembly and maturation of the capsid. In, Cytomegaloviruses: Molecular Biology and Immunology. Ed, M. Reddehase. Horizon Scientific Press, Norwich UK., 2006. Pub Med Reference not available
McCartney, S.A., Brignole, E.J., Kolegraff, K.N., Loveland, A.N., Ussin, L.M., and Gibson, W. Chemical rescue of I-site cleavage in living cells and in vitro discriminates between the cytomegalovirus protease, assemblin, and its precursor, pUL80a, J. Biol. Chem. 280:33206-33212, 2005. Pub Med Reference
Loveland, A.N., Chan, C.-K., Brignole, E.J., and Gibson, W. Cleavage of human cytomegalovirus protease pUL80a at internal and cryptic sites is not essential but enhances infectivity, J. Virol. 79:12961-12968, 2005. Pub Med Reference
- Wang, J., Loveland, A.N., Kattenhorn, L.M., Ploegh, H.L., and Gibson, W. High-molecular-weight protein (pUL48) of human cytomegalovirus is a competent deubiquitinating protease: Mutant viruses altered in its active-site cysteine or histidine are viable, J. Virol. 80:6003-6012, 2006. Pub Med Reference
- Loveland, A.N., Nang, L., Nguyen, N.L., Brignole, E.J., and Gibson, W. The amino-conserved domain of human cytomegalovirus UL80a proteins is required for key interactions during early stages of capsid formation and virus production, J. Virol. 81:620-628, 2007. Pub Med Reference
- Brignole, E.J. and Gibson, W. Enzymatic activities of human cytomegalovirus maturational protease assemblin and its precursor (pPR, pUL80a) are comparable: Maximal activity of pPR requires self-interaction through its scaffolding domain, J Virol. 81:4091-4103, 2007. Pub Med Reference
- Nguyen, N.L.., Loveland, A.N. , and Gibson, W. Nuclear localization sequences in cytomegalovirus capsid assembly proteins (UL80 proteins) are required or virus production: Inactivating NLS1, NLS2, or both affects replication to strikingly different extents. J. Virol. 82:5381-5389, 2008 Pub Med Reference
- Gibson, W. Structure and Formation of the Cytomegalovirus Virion. In, Human Cytomegalovirus (Eds., T. Shenk and M.F. Stinski), Current Topics in Microbiology and Immunology, Springer Press, 325:187-204, 2008.
- Kim, E. T., Oh, S. E., Lee, Y.O., Gibson, W., and Ahn, J.-H. Cleavage specificity of the UL48 deubiquitinating protease activity of human cytomegalovirus and the growth of an active site mutant virus in cultured cells. J. Virol., 83:12046-12056, 2009. Pub Med Reference
- Fernandes, S.M., Brignole, E.J. and Gibson, W. Cytomegalovirus capsid protease: Biological substrates are cleaved more efficiently by full-length enzyme (pUL80a) than by the catalytic domain (assemblin). J. Virol., 85:3526-3534, 2011. Pub Med Reference
- Gibson, W. Cytomegalovirus assemblin. In, Handbook of Proteolytic Enzymes, 3rd Edition (Eds. N. Rawlings and G. Salvesen), Elsevier (2013). Pub Med Reference Not Available.
- Gibson, W. and Bogner, E. Morphogenesis of the cytomegalovirus virion and subvirus particles. In, Cytomegaloviruses: From Molecular Pathogenesis to Intervention (Ed., M.J Reddehase), Norfolk, UK, Caister Academic Press, pp 230-246 (2013). Pub Med Reference Not Available
- Kalu, N.N., Desai, P., Shirley, C.M., Avery, R., Jones, R.J., Gibson, W., Dennis, P., and Ambinder, R.F. Nelfinavir inhibits maturation and export of herpes simplex virus type 1. J. Virol., 88:5455-5461, 2014. Pub Med Reference
Tullman, J.A., Harmon, M.-E., Delannoy, M., and Gibson, W. Recovery of an HMWP/hmwBP (pUL48/pUL47) complex from virions of human cytomegalovirus: subunit interactions, oligomers composition, deubiquitylase activity. J. Virol., 88:8256-8267, 2014. Pub Med Reference