Active site remodeling switches HIV specificity of antiretroviral TRIMCyp

Price, Amanda J.; Marzetta, Flavia; Lammers, Michael; Ylinen, Laura M. J.; Schaller, Torsten; Wilson, Sam J.; Towers, Greg J.; James, Leo C.

doi:10.1038/nsmb.1667

Cited by 93 publications

(127 citation statements)

References 39 publications

Supporting

Mentioning

117

Contrasting

Order By: Relevance

“…In the cases of CypA1 and CypA2, deviation from broad capsid-binding evolved within 6 My. Therefore, although broad capsid binding appears as a predisposed feature of CypA, the specificity that each CypA retrogene evolves is determined by minor changes that have a great impact on the capsid-binding trajectory (28,33,40). Based on our results with TRIM-parentalCypA, we predict that TRIMCypA3 was also capable of interacting with a broad range of lentiviral capsids on birth.…”

Section: Discussionmentioning

confidence: 91%

See 1 more Smart Citation

Birth, decay, and reconstruction of an ancient TRIMCyp gene fusion in primate genomes

Malfavon-Borja

Wu²,

Emerman³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

TRIM5 is a host antiviral gene with an evolutionary history of genetic conflict with retroviruses. The TRIMCyp gene encodes a protein fusion of TRIM5 effector domains with the capsid-binding ability of a retrotransposed CyclophilinA ( CypA ), resulting in novel antiviral specificity against lentiviruses. Previous studies have identified two independent primate TRIMCyp fusions that evolved within the past 6 My. Here, we describe an ancient primate TRIMCyp gene (that we call TRIMCypA3 ), which evolved in the common ancestor of simian primates 43 Mya. Gene reconstruction shows that CypA3 encoded an intact, likely active, TRIMCyp antiviral gene, which was subject to selective constraints for at least 10 My, followed by pseudogenization or loss in all extant primates. Despite its decayed status, we found TRIMCypA3 gene fusion transcripts in several primates. We found that the reconstructed “newly born” TrimCypA3 encoded robust and broad retroviral restriction activity but that this broad activity was lost via eight amino acid changes over the course of the next 10 My. We propose that TRIMCypA3 arose in response to a viral pathogen encountered by ancestral primates but was subsequently pseudogenized or lost due to a lack of selective pressure. Much like imprints of ancient viruses, fossils of decayed genes, such as TRIMCypA3 , provide unique and specific insight into paleoviral infections that plagued primates deep in their evolutionary history.

show abstract

Section: Discussionmentioning

confidence: 91%

“…Previous studies have explored the interactions between CypA genes and retrogenes with lentiviral capsids (15,(24)(25)(26)(27)(32)(33)(34). We were therefore interested in assessing whether ancient, potentially active versions of TRIMCyA3 might have interacted with lentiviral capsids.…”

Section: Testing Ancient and De Novo Trimcyp Proteins For Restriction Ofmentioning

confidence: 99%

Birth, decay, and reconstruction of an ancient TRIMCyp gene fusion in primate genomes

Malfavon-Borja

Wu²,

Emerman³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…For example, Defect A, which is present at both temperatures, abuts a loop that participates in a conformational exchange process observed by NMR (23). Mutations that change the local packing surrounding this void impact the loop conformation and modify the affinity of primate CypA homologs for the HIV capsid (24). In addition to the cavities present at both temperatures, the room-temperature structure contains several small packing defects (indicated by numbers in Fig.…”

Section: Resultsmentioning

confidence: 99%

Accessing protein conformational ensembles using room-temperature X-ray crystallography

Fraser

Bedem

Samelson

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

562

454

View full text Add to dashboard Cite

Modern protein crystal structures are based nearly exclusively on X-ray data collected at cryogenic temperatures (generally 100 K). The cooling process is thought to introduce little bias in the functional interpretation of structural results, because cryogenic temperatures minimally perturb the overall protein backbone fold. In contrast, here we show that flash cooling biases previously hidden structural ensembles in protein crystals. By analyzing available data for 30 different proteins using new computational tools for electron-density sampling, model refinement, and molecular packing analysis, we found that crystal cryocooling remodels the conformational distributions of more than 35% of side chains and eliminates packing defects necessary for functional motions. In the signaling switch protein, H-Ras, an allosteric network consistent with fluctuations detected in solution by NMR was uncovered in the room-temperature, but not the cryogenic, electron-density maps. These results expose a bias in structural databases toward smaller, overpacked, and unrealistically unique models. Monitoring room-temperature conformational ensembles by X-ray crystallography can reveal motions crucial for catalysis, ligand binding, and allosteric regulation.protein conformational dynamics | energy landscape | Ringer | qFit M acromolecular X-ray crystallographic diffraction experiments provide powerful insights into the relationship between structure and biological function. Although macromolecules populate vast ensembles of alternative conformational substates (1), crystallographic models depicting the major average conformation have provided foundational ideas about the mechanisms of biochemical reactions. By slowing radiation damage to the sample, crystal cooling has catalyzed a revolution in structural biology, enabling structure determinations from tiny crystals using bright synchrotron X-ray sources (2-4). It is estimated that more than 95% of the >65;000 crystal structures deposited in the Protein Data Bank (PDB) are based on cryogenic data (5).Crystal cooling is generally thought to introduce little bias in the functional interpretation of structural results. Some investigators have suggested that the standard practice of plunging crystals into liquid nitrogen and collecting X-ray diffraction data at 100 K traps a representative set of conformations populated at room temperature (6, 7). In contrast, early structural comparisons by Petsko, Frauenfelder, and colleagues indicated that cooling myoglobin crystals causes a small reduction in the protein volume due to anisotropic displacements of atomic positions and subtle changes of contacts between α-helices (8). A landmark study of crystalline ribonuclease A (RNaseA) by Tilton, Petsko, and coworkers revealed diverse temperature-dependent changes in the average structure, ranging from shrinkage at low temperatures to increased loop disorder at 47°C (9). A recent analysis comparing 15 room-temperature and cryogenic crystal structures documented that cryocooling generally increas...

show abstract

“…Recent works have focused on the interaction of Gag-CA and its counterpart (CypA, TRIM5 and a TRIM5/CypA fusion protein, TRIMCyp). It is well-established now that CypA, TRIM5 and TRIMCyp act as an inhibitor of HIV-1 replication in a species-specific manner (Lim et al, 2010;Luban, 2007;Nakayama & Shioda, 2010;Price et al, 2009;Towers, 2007;Ylinen, 2010). These cellular proteins exert their anti-viral powers on the incoming virion core in a poorly defined way (Table 3 and Fig.…”

Section: Gag-ca and Its Interacting Cellular Proteins (Cypa Trim5 Amentioning

confidence: 99%

Macaque-Tropic HIV-1 Derivatives: A Novel Experimental Approach to Understand Viral Replication and Evolution in Vivo

Nomaguchi¹,

Doi²,

Fujiwara³

et al. 2011

HIV-Host Interactions

View full text Add to dashboard Cite

Active site remodeling switches HIV specificity of antiretroviral TRIMCyp

Cited by 93 publications

References 39 publications

Birth, decay, and reconstruction of an ancient TRIMCyp gene fusion in primate genomes

Birth, decay, and reconstruction of an ancient TRIMCyp gene fusion in primate genomes

Accessing protein conformational ensembles using room-temperature X-ray crystallography

Macaque-Tropic HIV-1 Derivatives: A Novel Experimental Approach to Understand Viral Replication and Evolution in Vivo

Contact Info

Product

Resources

About