Retroviruses and other RNA viruses translate key proteins from a single mRNA relying on translational frameshift to produce concatenating protein domains called polyproteins before subsequent cleavage during maturation to produce mature and highly functional proteins. For HIV, a single mRNA is used to produce precursor structural polyproteins (Gag) and Gag-Pol which contains both the structural and enzymatic proteins via a -1 translational frameshift at the end of the gag gene, before a virally encoded protease (PR) cleaves them into their mature entities. For foamy viruses, a close relative of HIV and the most ancient retrovirus, the structural and enzymatic proteins are made from separate mRNAs using alternative splicing. This is followed by limited proteolysis to produce a mature Gag that is only ~ 3 kDa smaller than the immature Gag while the Pol is processed into protease-reverse transcriptase (PR-RT) fusion, and integrase (IN). This paradigm is different from other retroviruses where each structural and enzymatic protein is cleaved separately. Over the years, structures of the mature enzymes PR, RT, and IN have been crucial in our understanding of catalysis and development of antiretrovirals, but knowledge of the Pol precursor architecture and function before PR cleavage is limited. Crystal structure of the prototype foamy virus (PFV) PR-RT and cryo-EM structure of HIV-1 Pol will be presented in this talk. The PFV PR-RT remains monomeric with all known domains and subdomains of PR and RT present. On the hand, the PR-RT in HIV-1 Pol has a similar arrangement to the mature RT heterodimer, and its dimerization brings PR monomers close together to dimerize activating proteolytic processing. The IN domain remains unresolved in the structure. Thus, retroviruses likely leverage the dimerization interfaces in Pol to regulate assembly and maturation of polyprotein precursors.
Chasing an enigma: unravelling the mystery of retroviral polyproteins for potential drug development
Abstract
Speaker
Dr Jerry Joe Harrison
Structural and Chemical Biology Research Group, University of Ghana
About
My name is Jerry Joe Harrison, a Senior Lecturer in Medicinal Chemistry and Structural Biology at the University of Ghana. I hold a BSc and MPhil degrees in Chemistry from the University of Ghana and a Ph.D in Medicinal Chemistry from Rutgers University (USA). I undertook my Ph.D studies under the mentorship of Prof. Eddy Arnold as a Fulbright Scholar where I trained in structural biology and biophysical chemistry in the Department of Medicinal Chemistry.
I am formerly an HBNU global health fellow at the West African Centre for Cell Biology of Infectious Pathogens (WACCBIP) in Ghana, characterizing HIV-2 reverse transcriptase (RT)-nucleic acid and RT-nucleic acid-drug complexes. I have also recently been awarded a Crick African Network (CAN) career acceleration fellowship sponsored by LifeArc, UK, to study polyproteins and drug development for HIV-2. I lead the Structural and Chemical Biology research group at the University of Ghana. I have recently been elected as the President of the University Teachers’ Association at the University of Ghana.
Selected publications
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vancouver
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The Biophysics in Africa Monthly Colloquium Series is a joint project of the African Light Source Foundation (AfLS), African Physical Society (AfPS), and the South African Institute of Physics (SAIP). SAIP is an adhering body of the International Union of Pure and Applied Biophysics (IUPAB). The colloquia are always on the last Wednesday of every month. In addition to participation by students and colleagues worldwide, we invite speakers from around the globe as well. For more information please feel free to contact us at colloquium.series@africanbiophysics.org