Characterizing the Role of ORF6 in COVID-19
Faculty Scholar, Howard Hughes Medical Institute; Investigator, Heritage Medical Research Institute; Professor of Chemistry
Professor Andre Hoelz, a leading expert in establishing the structure-function of the Nuclear Pore Complex (NPC), is investing how the SARS-CoV-2 peptide ORF6 interacts with the NPC to hijack host cells and facilitate its own survival. Previous work on the closely related SARS-CoV-1 virus that caused SARS showed that one of its components, a peptide called ORF6, contributes to the attenuation of the host cell's immune response by targeting the nuclear transport factor karyopherin-a2. ORF6 is also present in SARS-CoV-2 and preliminary data from the UCSF COVID- 19 initiative show that it binds to components of the NPC called Rae1 and Nup98. Both findings suggest that ORF6 interferes with normal intracellular transport between the cytoplasm and nucleus, thereby contributing to SARS-CoV-2's hijacking of host cells, and thus representing a promising therapeutic target. As a first step toward developing novel COVID-19 therapies, the Hoelz lab is elucidating the molecular details of the interactions between SARS-CoV ORF6 and its cellular binding partners Rae1, Nup98 and karyopherin-a2 through biochemical and structural studies.
Preliminary data obtained by the Hoelz lab in the past two weeks supports the hypothesis that SARS-CoV-2 ORF6 forms an octameric plug in the central transport channel of the octameric NPC. Because each NPC contains 48 copies of Rae1•Nup98, multiple SARS-CoV2 ORF6 octamers could form a stack in the central transport channel. Such ORF6 octamer stacks could not only block mRNA export by competing with mRNA binding to Rae1 but also physically block the central transport channel by holding on to numerous Rae1 molecules with their ‘sticky' C-terminal regions. Moreover, karyopherin-alpha isoforms are known to bind to phenylalanine-glycine (FG) repeats in the central transport channel and their trapping by ORF6 could further exacerbate NPC blockage. The SARS-CoV2 ORF6 homo-octamer thus represent another high-priority target for structure determination, in addition to the complex structures between SARS-CoV- 2 ORF6 and Rae1•Nup98 and various karyopherins.
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