TRIM5? is a restriction factor which targets the retroviral capsid during infection which inhibits infection by inducing the abortive disassembly of the viral capsid core. The mechanism by which this occurs is poorly understood. We provide data demonstrating that dynamic conformational changes in TRIM5? correlate with the ability to inhibit viral infection, and propose to better define these conformational changes to understand the molecular interactions that drive capsid disassembly.
In aim 1, we will define the conformational changes that occur in rhesus TRIM5?, human TRIM5?, and a panel of naturally occurring and structurally guided mutations to define the molecular interactions that drive these conformational changes in the context of the recombinant TRIM5? dimeric unit comprising the coiled coil domain and linker 2 region.
In Aim 2, we will expand these studies to define how these conformational changes translate to neighboring domains, including the capsid binding SPRY domain of TRIM5?, and also determine how SPRY binding to assembled CA influences these conformational changes.
In aim 3, we propose functional validation of the results obtained in the first 2 aims in experiments which will determine how the biophysical and biochemical proteins translate to the ability to perform the individual, measurable steps in the restriction process.
This application seeks to understand how conformational changes in the TRIM5? restriction factor drive disassembly of the HIV-1 core. The understanding here will provide insight into the mechanism by which a host protein prevents viral infection, while also providing insight into the function of other TRIM family proteins, which are increasingly appreciated to play diverse roles in the development of cancer, inflammation and innate immune processes.
| Roganowicz, Marcin D; Komurlu, Sevnur; Mukherjee, Santanu et al. (2017) TRIM5? SPRY/coiled-coil interactions optimize avid retroviral capsid recognition. PLoS Pathog 13:e1006686 |
