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Journal of Virology, April 2009, p. 3365-3373, Vol. 83, No. 7
0022-538X/09/$08.00+0     doi:10.1128/JVI.00432-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

An Invariant Surface Patch on the TRIM5{alpha} PRYSPRY Domain Is Required for Retroviral Restriction but Dispensable for Capsid Binding{triangledown}

Sarah Sebastian,1 Christian Grütter,2 Caterina Strambio de Castillia,3 Thomas Pertel,3,4 Silvia Olivari,3 Markus G. Grütter,2 and Jeremy Luban1,3,4*

Department of Microbiology, Columbia University, New York, New York 10032,1 Department of Biochemistry, University of Zurich, CH-8057 Zurich, Switzerland,2 Institute for Research in Biomedicine, CH-6500 Bellinzona, Switzerland,3 Department of Microbiology and Molecular Medicine, University of Geneva, CH-1211 Geneva, Switzerland4

Received 27 February 2008/ Accepted 5 January 2009

TRIM5{alpha} is a retrovirus restriction factor in the host cell cytoplasm that blocks infection before provirus establishment. Restriction activity requires capsid (CA)-specific recognition by the PRYSPRY domain of TRIM5{alpha}. To better understand the restriction mechanism, nine charge-cluster-to-triple-alanine mutants in the TRIM5{alpha} PRYSPRY domain were assessed for CA-specific restriction activity. Five mutants distributed along the TRIM5{alpha} PRYSPRY primary sequence disrupted restriction activity against N-tropic murine leukemia virus and equine infectious anemia virus. Modeling of the TRIM5{alpha} PRYSPRY domain based on the crystal structures of PRYSPRY-19q13.4.1, GUSTAVUS, and TRIM21 identified a surface patch where disruptive mutants clustered. All mutants in this patch retained CA-binding activity, a reticular distribution in the cytoplasm, and steady-state protein levels comparable to those of the wild type. Residues in the essential patch are conserved in TRIM5{alpha} orthologues and in closely related paralogues. The same surface patch in the TRIM18 and TRIM20 PRYSPRY domains is the site of mutants causing Opitz syndrome and familial Mediterranean fever. These results indicate that, in addition to CA-specific binding, the PRYSPRY domain possesses a second function, possibly binding of a cofactor, that is essential for retroviral restriction activity by TRIM5{alpha}.

* Corresponding author. Mailing address: Department of Microbiology and Molecular Medicine, University of Geneva, CH-1211 Geneva, Switzerland. Phone and fax: 41-22-379-5720. E-mail: jeremy.luban{at}unige.ch

{triangledown} Published ahead of print on 19 January 2009.

Journal of Virology, April 2009, p. 3365-3373, Vol. 83, No. 7
0022-538X/09/$08.00+0     doi:10.1128/JVI.00432-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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