TRIM5alpha SPRY/coiled-coil interactions optimize avid retroviral capsid recognition Journal Article

Authors: Roganowicz, M. D.; Komurlu, S; Mukherjee, S; Plewka, J.; Alam, S. L.; Skorupka, K. A.; Wan, Y.; Dawidowski, D.; Cafiso, D. S.; Ganser-Pornillos, B. K.; Campbell, E. M.; Pornillos, O.
Article Title: TRIM5alpha SPRY/coiled-coil interactions optimize avid retroviral capsid recognition
Abstract: Restriction factors are important components of intrinsic cellular defense mechanisms against viral pathogens. TRIM5alpha is a restriction factor that intercepts the incoming capsid cores of retroviruses such as HIV and provides an effective species-specific barrier to retroviral infection. The TRIM5alpha SPRY domain directly binds the capsid with only very weak, millimolar-level affinity, and productive capsid recognition therefore requires both TRIM5alpha dimerization and assembly of the dimers into a multivalent hexagonal lattice to promote avid binding. Here, we explore the important unresolved question of whether the SPRY domains are flexibly linked to the TRIM lattice or more precisely positioned to maximize avidity. Biochemical and biophysical experiments indicate that the linker segment connecting the SPRY domain to the coiled-coil domain adopts an alpha-helical fold, and that this helical portion mediates interactions between the two domains. Targeted mutations were generated to disrupt the putative packing interface without affecting dimerization or higher-order assembly, and we identified mutant proteins that were nevertheless deficient in capsid binding in vitro and restriction activity in cells. Our studies therefore support a model wherein substantial avidity gains during assembly-mediated capsid recognition by TRIM5alpha come in part from tailored spacing of tethered recognition domains.
Journal Title: PLoS pathogens
Volume: 13
Issue: 10
ISSN: 1553-7374; 1553-7366
Publisher: Unknown  
Journal Place: United States
Date Published: 2017
Start Page: e1006686
Language: eng
Notes: LR: 20171219; GR: P50 GM082545/GM/NIGMS NIH HHS/United States; GR: R01 GM112508/GM/NIGMS NIH HHS/United States; JID: 101238921; 0 (Carrier Proteins); 0 (TRIM5 protein, human); 2017/05/03 00:00 [received]; 2017/10/10 00:00 [accepted]; 2017/11/02 00:00 [revised]; 2017/10/19 06:00 [pubmed]; 2017/11/14 06:00 [medline]; 2017/10/18 06:00 [entrez]; epublish