Mechanism of B-box 2 domain-mediated higher-order assembly of the retroviral restriction factor TRIM5α
| Autor: | Barbie K. Ganser-Pornillos, Gabriel A. Frank, Devin E. Christensen, Owen Pornillos, Ginna L Doss, Jonathan M. Wagner, Katarzyna Skorupka, Wesley I. Sundquist, Marcin D. Roganowicz, Yueping Wan, Steven L. Alam |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
QH301-705.5 Science viruses Protein domain Trimer restriction factor Biochemistry General Biochemistry Genetics and Molecular Biology Virus 03 medical and health sciences Retrovirus Protein structure Biology (General) protein structure chemistry.chemical_classification DNA ligase 030102 biochemistry & molecular biology General Immunology and Microbiology biology higher-order assembly General Neuroscience HIV General Medicine Biophysics and Structural Biology biology.organism_classification Virology 3. Good health Cell biology 030104 developmental biology Capsid Structural biology chemistry Medicine Other Rhesus Macaque Research Article |
| Zdroj: | eLife eLife, Vol 5 (2016) |
| ISSN: | 2050-084X |
| DOI: | 10.7554/elife.16309 |
| Popis: | Restriction factors and pattern recognition receptors are important components of intrinsic cellular defenses against viral infection. Mammalian TRIM5α proteins are restriction factors and receptors that target the capsid cores of retroviruses and activate ubiquitin-dependent antiviral responses upon capsid recognition. Here, we report crystallographic and functional studies of the TRIM5α B-box 2 domain, which mediates higher-order assembly of TRIM5 proteins. The B-box can form both dimers and trimers, and the trimers can link multiple TRIM5α proteins into a hexagonal net that matches the lattice arrangement of capsid subunits and enables avid capsid binding. Two modes of conformational flexibility allow TRIM5α to accommodate the variable curvature of retroviral capsids. B-box mediated interactions also modulate TRIM5α’s E3 ubiquitin ligase activity, by stereochemically restricting how the N-terminal RING domain can dimerize. Overall, these studies define important molecular details of cellular recognition of retroviruses, and how recognition links to downstream processes to disable the virus. DOI: http://dx.doi.org/10.7554/eLife.16309.001 eLife digest After infecting a cell, a virus reprograms the cell to produce new copies of the virus, which then spread to other cells. However, cells have evolved ways to fight back against this infection. For example, many mammalian cells contain proteins called restriction factors that prevent the virus from multiplying. The TRIM5 proteins form one common set of restriction factors that act against a class of viruses called retroviruses. HIV-1 and related retroviruses have a protein shell known as a capsid that surrounds the genetic material of the virus. The capsid contains several hundred repeating units, each of which consists of a hexagonal ring of six capsid proteins. Although this basic pattern is maintained across different retroviruses, the overall shape of the capsids can vary considerably. For instance, HIV-1 capsids are shaped like a cone, but other retroviruses can form cylinders or spheres. Soon after a retrovirus enters a mammalian cell, TRIM5 proteins bind to the capsid. This causes the capsid to be destroyed, which prevents replication of the virus. Previous research has shown that many TRIM5 proteins must link up with each other via a region of their structure called the 'B-box 2' domain in order to efficiently recognize capsids. How this assembly process occurs, and why it enables the TRIM5 proteins to recognize different capsids was not fully understood. Now, Wagner et al. (and independently Li, Chandrasekaran et al.) have investigated these questions. Wagner et al. engineered short versions of a type of TRIM5 protein called TRIM5α and used a technique called X-ray crystallography to determine the structure of its B-box domain. This revealed that the B-box present in one molecule of TRIM5α can associate with the B-boxes on two other TRIM5α molecules. By working in groups of three (or trimers), the B-box domains connect several TRIM5α proteins to form a hexagonal net. The TRIM5α net matches the arrangement of the capsid proteins in the shell of the virus, which enables TRIM5α to bind strongly to HIV-1 capsids. Wagner et al. also found that B-box trimers are flexible, which allows the TRIM5α net to adapt to the shape of the HIV-1 capsid and wrap around regions where it curves. In addition, computer modelling suggested that the B-box trimer may also enable TRIM5α to carry out the next steps in the process of disabling the virus. Further work is now needed to understand in more detail how the trimers have this effect. DOI: http://dx.doi.org/10.7554/eLife.16309.002 |
| Databáze: | OpenAIRE |
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