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Principal Investigator: Kyung Lee
Organization: DIVISION OF BASIC SCIENCES - NCI
Fiscal Year: 2021
Award: $224,347
Funding agency: National Cancer Institute
Our unbiased proteomic mass spectrometry and subsequent biochemical analyses showed that Plk4 binds to the C-terminal acidic domain (1401-1507) of a cellular scaffold protein, VprBP, via its C-terminal cryptic polo-box. Strikingly, HIV-1 Vpr, which binds to the WD40 domain (1003-1400) of VprBP, greatly enhanced the VprBP-Plk4 interaction and induced the formation of the Vpr-VprBP-Plk4 complex. All three proteins colocalized to centrosomes and the formation of the ternary complex appeared to augment Plk4-mediated centriole duplication. Consistent with these findings, VprBP promoted Plk4 function by stabilizing its centriole-associated state rather than inducing its proteasomal degradation, as was observed for the Vpx-VprBP-SAMHD1 complex and other cellular targets. These data suggest that, when cells are infected with HIV-1, Vpr may alter Plk4's function by forming the Vpr-VprBP-Plk4 complex under physiological conditions and induce Plk4-dependent centriole overduplication, a cellular event causing aneuploidy and cancer. A structurally related HIV-2 Vpx failed to interact with VprBP and Plk4, indicating the specificity of HIV-1 Vpr-induced events. Based on these observations, we postulate that HIV-1 Vpr can directly alter genomic stability and facilitate carcinogenesis by hijacking the cellular Plk4-VprBP complex. Additional studies are planned to determine the role of the ternary Vpr-VprBP-Plk4 complex under physiologically relevant conditions, using HIV-1-susceptible cells and tissues in animal models. This research could shed light on the mechanism that could directly link HIV/AIDS to the etiology of its comorbid cancers. Furthermore, it may offer a new paradigm in understanding the increased cancer risk in people living with HIV-1. Investigating HIV-induced comorbidities is one of the four designated NIH HIV/AIDS research priorities. This research is designed to directly address HIV-1-associated cancer comorbidities. We have gained an enriched experience in studying how HIV proteins interact with cellular targets and alter cell physiology using various biochemical and structure-based analyses. Investigation into the way in which SARS-CoV-2 (COVID-19) recognizes its human cell surface receptor and isolation of small molecular inhibitors that disrupt this event would be critical for the intervention of viral entry into host cells. The exceptional high-affinity interaction between the COVID-19 spike protein (S protein) and the human extracellular receptor, ACE2, underlies the widespread pandemic of COVID-19. We are seeking to establish a specific COVID-19 S protein-ACE2 interaction trap using a membrane protein-friendly lipid-bilayer platform to isolate and develop small molecule inhibitors against COVID-19 entry into host cells.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV S protein><2019-nCoV spike glycoprotein><2019-nCoV spike protein><ACE2><AIDS><AIDS Virus><AIDS/HIV><AIDS/HIV problem><Acquired Immune Deficiency><Acquired Immune Deficiency Syndrome><Acquired Immune Deficiency Syndrome Virus><Acquired Immuno-Deficiency Syndrome><Acquired Immunodeficiency Syndrome><Acquired Immunodeficiency Syndrome Virus><Acquired Immunologic Deficiency Syndrome><Address><Affinity><Aneuploid><Aneuploidy><Animal Model><Animal Models and Related Studies><Assay><Binding><Bioassay><Biochemical><Biologic Assays><Biological><Biological Assay><Body Tissues><C-terminal><COVID crisis><COVID epidemic><COVID pandemic><COVID-19><COVID-19 S protein><COVID-19 crisis><COVID-19 epidemic><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 pandemic><COVID-19 public health crisis><COVID-19 spike glycoprotein><COVID-19 spike protein><COVID-19 virus><COVID19><COVID19 S protein><COVID19 crisis><COVID19 epidemic><COVID19 global health crisis><COVID19 global pandemic><COVID19 health crisis><COVID19 pandemic><COVID19 public health crisis><COVID19 spike glycoprotein><COVID19 spike protein><COVID19 virus><CV-19><CV19><Cancer Induction><Cancers><Causality><Cell Body><Cell Cycle><Cell Division Cycle><Cell Function><Cell Process><Cell Surface Receptors><Cell model><Cell physiology><Cells><Cellular Function><Cellular Physiology><Cellular Process><Cellular model><Centrioles><Centrosome><CoV-2><CoV2><Complex><Cultured Cells><Data><Development><Electron Microscopy><Etiology><Event><G-Beta Repeat><Genome Stability><Genomic Stability><Goals><HIV><HIV-1><HIV-2><HIV-I><HIV-II><HIV/AIDS><HIV/AIDS problem><HIV1><HIV2><HTLV-IV><Human><Human Immunodeficiency Virus Type 1><Human Immunodeficiency Virus Type 2><Human Immunodeficiency Viruses><Human T-Lymphotropic Virus Type IV><Human immunodeficiency virus 1><Human immunodeficiency virus 2><Immune system><Incidence><Infection><Intervention><Intervention Strategies><Investigation><Kinases><LAV-2><LAV-HTLV-III><Lead><Light><Link><Lipid Bilayers><Lymphadenopathy-Associated Virus><Malignant Neoplasms><Malignant Tumor><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Mediating><Membrane Protein Gene><Membrane Proteins><Membrane-Associated Proteins><Modern Man><Molecular><Molecular Interaction><NIH><National Institutes of Health><Nature><Organelles><PLK Gene><PLK1><PLK1 gene><Pathogenesis><Pb element><Persons><Phosphotransferase Gene><Phosphotransferases><Photoradiation><Physiologic><Physiological><Polo-Like Kinase><Process><Proteins><Proteomics><Receptor Protein><Research><Research Priority><Risk><Role><SARS corona virus 2><SARS-CoV-2><SARS-CoV-2 S protein><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 pandemic><SARS-CoV-2 spike glycoprotein><SARS-CoV-2 spike protein><SARS-CoV2><SARS-CoV2 S protein><SARS-CoV2 epidemic><SARS-CoV2 pandemic><SARS-CoV2 spike glycoprotein><SARS-CoV2 spike protein><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><STPK13><Scaffolding Protein><Serine/Threonine Protein Kinase 13><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 S protein><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 pandemic><Severe acute respiratory syndrome coronavirus 2 spike glycoprotein><Severe acute respiratory syndrome coronavirus 2 spike protein><Severe acute respiratory syndrome related corona virus 2><Single Crystal Diffraction><Specificity><Structure><Subcellular Process><Surface Proteins><Tissues><Transphosphorylases><Trp-Asp Repeat><Tryptophan-Aspartate Repeat><United States National Institutes of Health><Viral><Virus-HIV><WD Domain><WD Repeat><WD40 Domain><Wuhan coronavirus><X Ray Crystallographies><X-Ray Crystallography><X-Ray Diffraction Crystallography><X-Ray/Neutron Crystallography><Xray Crystallography><allergic/immunologic body system><allergic/immunologic organ system><angiotensin converting enzyme 2><angiotensin converting enzyme II><base><cancer risk><carcinogenesis><causation><cellular targeting><chromosomal missegregation><chromosome missegregation><co-morbid><co-morbidity><comorbidity><corona virus disease 2019><corona virus disease 2019 epidemic><corona virus disease 2019 pandemic><coronavirus disease 2019><coronavirus disease 2019 S protein><coronavirus disease 2019 crisis><coronavirus disease 2019 epidemic><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 pandemic><coronavirus disease 2019 public health crisis><coronavirus disease 2019 spike glycoprotein><coronavirus disease 2019 spike protein><coronavirus disease 2019 virus><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease pandemic><cryogenics><design><designing><developmental><disease causation><experience><extracellular><hCoV19><heavy metal Pb><heavy metal lead><high risk><interventional strategy><lipid bilayer membrane><malignancy><model of animal><model organism><nCoV2><neoplasm/cancer><new approaches><novel approaches><novel strategies><novel strategy><polo-like kinase 1><receptor><scaffold><scaffolding><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><small molecular inhibitor><small molecule inhibitor><social role>