Structural and Functional Integration of TRIM5alpha Domains for HIV Capsid Binding

University Of Virginia, Charlottesville VA

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Abstract

? DESCRIPTION (provided by applicant): The Tripartite Motif (TRIM) proteins are important components of first line cellular defense mechanisms against invading viruses. One TRIM family member, TRIM5?, directly binds and disassembles incoming human immunodeficiency virus (HIV) cores, preventing reverse transcription and inhibiting viral replication. At the same time, TRIM5? acts as a pattern recognition receptor that stimulates downstream proinflammatory signaling pathways. In order to accomplish these, TRIM5? first dimerizes through its coiled-coil domain and the dimers further assemble via their B-box 2 domains into a two-dimensional hexagonal lattice that surrounds HIV core particles. The hexagonal lattice contains regularly spaced capsid binding SPRY domains that mediate direct interactions with the proteinaceous HIV capsid shell. Each individual SPRY domain interacts very weakly, but the assembled TRIM network binds avidly by aligning SPRY domains with regularly spaced capsid epitopes. Recent structures of individual TRIM5? domains have suggested that the spacing and orientation of SPRY domains in TRIM5? might be controlled by a four-way packing interaction between two SPRY domains resting on two coiled-coil domains. However, a structure of the TRIM5? dimer including both coiled-coil and SPRY domains is necessary to confirm this. Furthermore, it appears that SPRY domains may be able to release from the coiled-coil domains with the intervening linker 2 regions acting as a flexible tether. This study will investigate the structureof the TRIM5? coiled-coil and SPRY dimer and the dynamic movements that may be associated with HIV capsid binding. We expect to discover the locations and orientations of capsid binding SPRY domains within the network surrounding HIV capsid particles. This will inform our understanding of the molecular defenses used by the cell to destroy viruses and may ultimately improve our ability to design therapeutics that mimic or complement these complex cellular machines.