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Structure of the Rhesus Monkey Trim5α PRYSPRY Domain, the HIV Capsid Recognition Module

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Structure of the Rhesus Monkey Trim5α PRYSPRY Domain, the HIV Capsid Recognition Module Structure of the rhesus monkey TRIM5α PRYSPRY domain, the HIV capsid recognition module Nikolaos Birisa, Yang Yangb, Alexander B. Taylora, Andrei Tomashevskia, Miao Guoa, P. John Harta,c, Felipe Diaz-Grifferob, and Dmitri N. Ivanova,d,1 aDepartment of Biochemistry and dCancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229; bDepartment of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461; and cGeriatric Research, Education, and Clinical Center, Department of Veterans Affairs, South Texas Veterans Health Care System, San Antonio, TX 78229 Edited by* Stephen P. Goff, Columbia University College of Physicians and Surgeons, New York, NY, and approved June 15, 2012 (received for review February 28, 2012) Tripartite motif protein TRIM5α blocks retroviral replication after pandemic when the simian immunodeficiency virus (SIV) passed cell entry, and species-specific differences in its activity are deter- from chimpanzees into a human host (1, 8, 9, 14). mined by sequence variations within the C-terminal B30.2/ TRIM5α binds to the assembled capsid of the mature viral core PRYSPRY domain. Here we report a high-resolution structure of a rather than the monomeric capsid protein, suggesting that TRI- TRIM5α PRYSPRY domain, the PRYSPRY of the rhesus monkey TRI- M5α may act as a pattern-recognition molecule (4, 8, 9). Remark- M5α that potently restricts HIV infection, and identify features in- ably, an EM investigation revealed that the purified tripartite volved in its interaction with the HIV capsid. The extensive capsid- motif of TRIM5α forms hexagonal arrays that match the symme- binding interface maps on the structurally divergent face of the try of the assembled retroviral capsid (15, 16). This observation protein formed by hypervariable loop segments, confirming that suggested a model of TRIM5α–capsid interaction, in which the TRIM5α evolution is largely determined by its binding specificity. hexagonal assembly of TRIM5α would juxtapose the PRYSPRY Interactions with the capsid are mediated by flexible variable loops domains with the regularly spaced epitopes on the surface of the via a mechanism that parallels antigen recognition by IgM antibo- assembled capsid, leading to specific, high-affinity binding of dies, a similarity that may help explain some of the unusual func- TRIM5α to the retroviral core. Mutations that interfere with tional properties of TRIM5α. Distinctive features of this pathogen- TRIM5α self-association also disrupt capsid cosedimentation BIOPHYSICS AND recognition interface, such as structural plasticity conferred by the confirming the importance of TRIM5α multimerization and the COMPUTATIONAL BIOLOGY mobile v1 segment and interaction with multiple epitopes, may avidity effect in capsid recognition (15, 17–19). Such multivalent, allow restriction of divergent retroviruses and increase resistance high-avidity interactions pose significant experimental chal- to capsid mutations. lenges. The binding of the individual PRYSPRY domains to the capsid surface may be very weak, which may be one of the – etroviral restriction factors are important components of in- reasons why direct PRYSPRY capsid interactions have not yet Rnate immunity defenses that protect higher organisms against been demonstrated by biochemical, biophysical, or structural retroviral pathogens. The splicing variant alpha of tripartite motif means despite the extensive mutagenesis and evolutionary data – five (TRIM5α) is particularly remarkable because of the potent suggesting a PRYSPRY capsid interface. activity that the TRIM5α of rhesus monkey (rhTRIM5α) displays The arrangement of the HIV capsid protein in the mature against HIV-1 (1). TRIM5α is a member of the tripartite motif retroviral core is well-characterized, and the atomic-resolution model of the entire assembled structure is now available (20); (TRIM) family of proteins increasingly recognized for their role α in innate immunity (2–4). All TRIM proteins share a conserved in contrast, structures of the primate TRIM5 PRYSPRY N-terminal tripartite domain motif consisting of a RING domain, domains have remained elusive, limiting our insight into capsid recognition by TRIM5α. Here we describe the structure of the followed by one or two B-box domains and then by a coiled-coil α segment. The composition of the C-terminal part of TRIMs var- rhesus TRIM5 PRYSPRY domain determined by a hybrid ies, and about one half of approximately 100 TRIM proteins in experimental approach that combines NMR spectroscopy and X-ray crystallography. The structure, NMR titration experiments, the human genome contain a C-terminal PRYSPRY domain (also – known as B30.2 domain), a protein-protein interaction module and site-directed mutagenesis suggest an extensive capsid (2, 3, 5). PRYSPRY interface dominated by the highly mobile v1 loop Rhesus TRIM5α is a cytoplasmic protein that normally blocks of the PRYSPRY domain. The capsid recognition mechanism, HIV replication after cell entry but prior to completion of reverse which is reminiscent of antigen recognition by the natural and the transcription (1). Viral determinants of susceptibility to TRIM5α- early immune response antibodies because it also involves mobile variable loops and high-avidity binding, may facilitate restriction mediated restriction are located within the capsid protein (6, 7), α and the restriction potency correlates with the ability of the of divergent retroviruses and increase resistance of TRIM5 to cytosolic TRIM5α to cosediment with the assembled viral capsid capsid mutations. (8, 9), strongly suggesting that direct interactions of TRIM5α with the viral capsid are required for restriction. The PRYSPRY do- Author contributions: N.B., Y.Y., A.B.T., A.T., M.G., F.D.-G., and D.N.I. designed research; main of TRIM5α is believed to form most of the capsid–TRIM5α N.B., Y.Y., A.B.T., A.T., M.G., F.D.-G., and D.N.I. performed research; N.B., Y.Y., A.B.T., interface as species-specific sequence variations within the A.T., M.G., P.J.H., F.D.-G., and D.N.I. analyzed data; and N.B., A.B.T., P.J.H., F.D.-G., and D.N.I. wrote the paper. PRYSPRY domain account for differences in the viral specificity of the TRIM5α-mediated restriction (10–12). In fact, the TRI- The authors declare no conflict of interest. M5α PRYSPRY domains contain some of the most rapidly chan- *This Direct Submission article had a prearranged editor. ging protein segments within primate genomes, an illustration of Data deposition: The crystallography, atomic coordinates, and structures factors have been deposited in the Protein Data Bank (PDB), www.pdb.org (PDB ID codes 3UV9 and 2LM3). how the evolutionary antagonism between retroviruses and their The chemical shift data have been deposited in the Biological Magnetic Resonance Data primate hosts accelerates remodeling of the host-pathogen inter- Bank (BMRB code: 18097). face (13). Most notably, recent evolution of the human TRIM5α 1To whom correspondence should be addressed. E-mail: [email protected]. PRYSPRY domain resulted in the variant that has poor affinity This article contains supporting information online at www.pnas.org/lookup/suppl/ for the HIV capsid, the vulnerability that contributed to the AIDS doi:10.1073/pnas.1203536109/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1203536109 PNAS Early Edition ∣ 1of6 Downloaded by guest on October 2, 2021 Results contacts. The pairwise interproton distance restraints obtained Structure and Dynamics of the rhTRIM5α PRYSPRY. Production of the from the NOE data limit the number of conformations that the recombinant TRIM5α PRYSPRY domain in bacterial expression v1 region can possibly adopt. The resulting hybrid X-ray/NMR systems is impeded by the low total protein expression and by the structure is shown in Fig. 1B. The v1 loop protrudes from the low soluble-to-insoluble protein ratio. Two features of our protein otherwise globular PRYSPRY domain and can adopt multiple expression strategy were important for high yields of soluble re- divergent conformations without violating the NOE-derived re- combinant protein: (i) codon optimization of TRIM5α sequences straints. These findings are consistent with the mobility of the and protein expression in the BL21 Rosetta 2 (EMD/Novagen) v1 segment apparent from the relaxation measurements. bacterial strains and (ii) use of the N-terminal solubility enhance- ment tag derived from the B1 domain of protein G (GB1) (21). Structural Evolution of PRYSPRY Domains. Comparison of the TRI- Detailed description of protein production and crystallization can M5α PRYSPRY structure to other known PRYSPRY structures be found in SI Experimental Procedures. offers insights into the molecular evolution of the primate TRI- The wild type version of rhTRIM5α PRYSPRY was refractory M5α and the expansion of PRYSPRY-containing TRIM proteins to crystallization; therefore, we used NMR to identify mobile seg- within the genomes of higher organisms. TRIM21 is the closest ments within PRYSPRY that could interfere with protein crystal evolutionary cousin of TRIM5α for which the PRYSPRY struc- packing. Measurement of the relaxation parameters of the pro- ture is known, and the interactions with its binding partner, the tein backbone amides revealed that the v1 variable loop of the invariant Fc segment of IgG, have been biochemically and struc- PRYSPRY domain was indeed highly mobile (Fig. 1A). Analysis turally characterized (24, 25). Structural comparison of the of the relaxation data
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