Catalysis of cis/trans isomerization in native HIV-1 capsid by human cyclophilin A

Bosco, Daryl A.; Eisenmesser, Elan; Pochapsky, Susan Sondej; Sundquist, Wesley I.; Kern, Dorothee

doi:10.1073/pnas.082100499

Cited by 202 publications

(234 citation statements)

References 63 publications

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“…NMR exchange spectroscopy, previously used to characterize the CypA-catalyzed cis/trans isomerization of the Gly 221 -Pro 222 peptide bond in the HIV capsid (14,15), indeed provided direct evidence for the catalytic activity of the cyclophilins and allowed us to assign the effect to individual prolyl bonds. Because of the unstructured nature of NS5A-D2 and the resulting low proton amide dispersion, 1 H, 15 N heteronuclear z-exchange spectroscopy (49) proved to be superior to 1 H, 1 H homonuclear EXSY spectroscopy and allowed us for the first time to prove in vitro that HCV NS5A-D2 is a substrate for the PPIase activity of at least two host cyclophilins ( Fig.…”

Section: Discussionmentioning

confidence: 99%

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Hepatitis C Virus NS5A Protein Is a Substrate for the Peptidyl-prolyl cis/trans Isomerase Activity of Cyclophilins A and B

Hanoulle

Badillo

Wieruszeski

et al. 2009

Journal of Biological Chemistry

153

196

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We report here a biochemical and structural characterization of domain 2 of the nonstructural 5A protein (NS5A) from the JFH1 Hepatitis C virus strain and its interactions with cyclophilins A and B (CypA and CypB). Gel filtration chromatography, circular dichroism spectroscopy, and finally NMR spectroscopy all indicate the natively unfolded nature of this NS5A-D2 domain. Because mutations in this domain have been linked to cyclosporin A resistance, we used NMR spectroscopy to investigate potential interactions between NS5A-D2 and cellular CypA and CypB. We observed a direct molecular interaction between NS5A-D2 and both cyclophilins. The interaction surface on the cyclophilins corresponds to their active site, whereas on NS5A-D2, it proved to be distributed over the many proline residues of the domain. NMR heteronuclear exchange spectroscopy yielded direct evidence that many proline residues in NS5A-D2 form a valid substrate for the enzymatic peptidyl-prolyl cis/trans isomerase (PPIase) activity of CypA and CypB.

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Section: Discussionmentioning

confidence: 99%

“…6). For comparison, Bosco et al (14,15) have found that with an enzyme:substrate ratio comparable to that used here, the CypA-catalyzed cis/trans isomerization of the Gly 221 -Pro…”

mentioning

confidence: 99%

Hepatitis C Virus NS5A Protein Is a Substrate for the Peptidyl-prolyl cis/trans Isomerase Activity of Cyclophilins A and B

Hanoulle

Badillo

Wieruszeski

et al. 2009

Journal of Biological Chemistry

153

196

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“…18 and 19). The cis-trans isomerization is catalyzed by CypA and Nup358Cyp (18,19). The uncatalyzed reaction is slow (exchange rates of <0.1 s −1 ), whereas in the presence of CypA and NUP358Cyp, isomerization rates of 6.6 and 12.1 s −1 were observed, respectively.…”

Section: Significancementioning

confidence: 99%

Dynamic allostery governs cyclophilin A–HIV capsid interplay

Hou

Zhang

et al. 2015

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

153

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Host factor protein Cyclophilin A (CypA) regulates HIV-1 viral infectivity through direct interactions with the viral capsid, by an unknown mechanism. CypA can either promote or inhibit viral infection, depending on host cell type and HIV-1 capsid (CA) protein sequence. We have examined the role of conformational dynamics on the nanosecond to millisecond timescale in HIV-1 CA assemblies in the escape from CypA dependence, by magic-angle spinning (MAS) NMR and molecular dynamics (MD). Through the analysis of backbone 1H-15N and 1H-13C dipolar tensors and peak intensities from 3D MAS NMR spectra of wild-type and the A92E and G94D CypA escape mutants, we demonstrate that assembled CA is dynamic, particularly in loop regions. The CypA loop in assembled wild-type CA from two strains exhibits unprecedented mobility on the nanosecond to microsecond timescales, and the experimental NMR dipolar order parameters are in quantitative agreement with those calculated from MD trajectories. Remarkably, the CypA loop dynamics of wild-type CA HXB2 assembly is significantly attenuated upon CypA binding, and the dynamics profiles of the A92E and G94D CypA escape mutants closely resemble that of wild-type CA assembly in complex with CypA. These results suggest that CypA loop dynamics is a determining factor in HIV-1's escape from CypA dependence.

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“…It normally resides in the cytoplasm and is known to regulate a wide range of cellular activities dependent on or independent of the enzyme activity (28,29). hCyPA can also be assembled into the viral particles of HIV and a few other viruses to facilitate viral replications (30,31).…”

mentioning

confidence: 99%

Regulation of Nuclear Translocation of the Myb1 Transcription Factor by TvCyclophilin 1 in the Protozoan Parasite Trichomonas vaginalis

Hsu

Chu

Wang

et al. 2014

Journal of Biological Chemistry

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Catalysis of cis/trans isomerization in native HIV-1 capsid by human cyclophilin A

Cited by 202 publications

References 63 publications

Hepatitis C Virus NS5A Protein Is a Substrate for the Peptidyl-prolyl cis/trans Isomerase Activity of Cyclophilins A and B

Hepatitis C Virus NS5A Protein Is a Substrate for the Peptidyl-prolyl cis/trans Isomerase Activity of Cyclophilins A and B

Dynamic allostery governs cyclophilin A–HIV capsid interplay

Regulation of Nuclear Translocation of the Myb1 Transcription Factor by TvCyclophilin 1 in the Protozoan Parasite Trichomonas vaginalis

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