Abstract
Gag proteins underlie retroviral replication by fulfilling numerous functional roles at various stages during viral life cycle. Out of the four mature proteins, Gag-capsid (CA) is a major component of viral particles, and has been most well studied biogenetically, biochemically and structurally. Gag-CA is composed of two structured domains, and also of a short stretch of disordered and flexible interdomain linker. While the two domains, namely, N-terminal and C-terminal domains (NTD and CTD), have been the central target for Gag research, the linker region connecting the two has been poorly studied. We recently have performed systemic mutational analyses on the Gag-CA linker region of HIV-1 by various experimental and in silico systems. In total, we have demonstrated that the linker region acts as a cis-modulator to optimize the Gag-related viral replication process. We also have noted, during the course of conducting the research project, that HIV-1 and SIVmac, belonging to distinct primate lentiviral lineages, share a similarly biologically active linker region with each other. In this brief article, we summarize and report the results obtained by mutational studies that are relevant to the functional significance of the interdomain linker of HIV/SIV Gag-CA. Based on this investigation, we discuss about the future directions of the research in this line.
Highlights
Gag is a main viral protein initially synthesized as a precursor in cells infected with retroviruses (Freed and Martin, 2013; Goff, 2013)
Experimental and in silico evidence supports the notion that the linker region optimizes Gag assembly, progeny virus production, and viral early infectivity by remotely regulating various interactions among CA-NTD and CA-CTD (Koma et al, 2019; this report)
The interdomain linker connecting two structured domains of Hsp70, a totally distinct cellular protein from viral Gag-CA, has been recently reported to act as a dynamic switch that allosterically regulates the interaction between the two domains (English et al, 2017)
Summary
Gag is a main viral protein initially synthesized as a precursor in cells infected with retroviruses (Freed and Martin, 2013; Goff, 2013). It was quite unclear how important or critical the interdomain linker region of HIV-1 Gag-CA is for Gag assembly, virus production, and viral early infectivity. STRUCTURAL REGULATION OF HIV GAG-CA FOR VIRAL REPLICATION BY ITS INTERDOMAIN LINKER REGION
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