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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM112508-01
Application #
8788597
Study Section
AIDS Molecular and Cellular Biology Study Section (AMCB)
Program Officer
Sakalian, Michael
Project Start
2014-09-15
Project End
2018-07-31
Budget Start
2014-09-15
Budget End
2015-07-31
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Virginia
Department
Physiology
Type
Schools of Medicine
DUNS #
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
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