Tripartite motif or TRIM proteins comprise the largest superfamily of RING-domain E3 ubiquitin ligases. These enzymes function in a wide variety of important cellular processes, particularly in innate antiviral response mechanisms. A defining feature of TRIM proteins is that they are composed of multiple domains, with each domain conferring a specific biochemical functionality to the protein. For these studies, we have a special focus on TRIM5j, which functions in the cell as a restriction factor that inhibits HIV-1 replication. We propose to: (1) Determine the structure of a complete tripartite motif in order to understand the molecular details of how the different constituent domains integrate structurally with each other. We will also determine the molecular principles that govern dimerization and higher-order assembly, which are important elements of TRIM protein function. (2) Define how the different domains of TRIM5j coordinate their biochemical activities, in order to recognize the incoming capsids of HIV-1 and restrict viral replication. We will use a multi-component, integrative approach that combines structural, biochemical, and cell biological techniques. The expected outcome is a comprehensive, molecular level understanding of TRIM5j-mediated inhibition of HIV-1 replication.
The principal goal of this project is to understand the structural organization of multi-domain ubiquitin E3 ligase enzymes of the tripartite motif (TRIM) protein family. In particular, we seek a detailed, molecular level understanding of how the different domains of the anti-viral TRIM5j protein integrate their different biochemical activitiesto inhibit HIV-1 replication. Our studies also have broad relevance to public health, since the molecular principles of TRIM5j are also directly applicable to other TRIM proteins, including ones that are implicated in developmental disorders and cancer.
|Wagner, Jonathan M; Christensen, Devin E; Bhattacharya, Akash et al. (2018) General Model for Retroviral Capsid Pattern Recognition by TRIM5 Proteins. J Virol 92:|
|Sanchez, Jacint G; Sparrer, Konstantin M J; Chiang, Cindy et al. (2018) TRIM25 Binds RNA to Modulate Cellular Anti-viral Defense. J Mol Biol 430:5280-5293|
|Janczyk, Pawe? ?; Skorupka, Katarzyna A; Tooley, John G et al. (2017) Mechanism of Ska Recruitment by Ndc80 Complexes to Kinetochores. Dev Cell 41:438-449.e4|
|Dawidziak, Daria M; Sanchez, Jacint G; Wagner, Jonathan M et al. (2017) Structure and catalytic activation of the TRIM23 RING E3 ubiquitin ligase. Proteins 85:1957-1961|
|Roganowicz, Marcin D; Komurlu, Sevnur; Mukherjee, Santanu et al. (2017) TRIM5? SPRY/coiled-coil interactions optimize avid retroviral capsid recognition. PLoS Pathog 13:e1006686|
|Sparrer, Konstantin M J; Gableske, Sebastian; Zurenski, Matthew A et al. (2017) TRIM23 mediates virus-induced autophagy via activation of TBK1. Nat Microbiol 2:1543-1557|
|Wagner, Jonathan M; Roganowicz, Marcin D; Skorupka, Katarzyna et al. (2016) Mechanism of B-box 2 domain-mediated higher-order assembly of the retroviral restriction factor TRIM5?. Elife 5:|
|Sanchez, Jacint G; Chiang, Jessica J; Sparrer, Konstantin M J et al. (2016) Mechanism of TRIM25 Catalytic Activation in the Antiviral RIG-I Pathway. Cell Rep 16:1315-1325|
|Li, Yen-Li; Chandrasekaran, Viswanathan; Carter, Stephen D et al. (2016) Primate TRIM5 proteins form hexagonal nets on HIV-1 capsids. Elife 5:|
|Sanchez, Jacint G; Okreglicka, Katarzyna; Chandrasekaran, Viswanathan et al. (2014) The tripartite motif coiled-coil is an elongated antiparallel hairpin dimer. Proc Natl Acad Sci U S A 111:2494-9|