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Research Article

Structural and Biochemical Characterization of the Human Cyclophilin Family of Peptidyl-Prolyl Isomerases

  • Tara L. Davis,

    Affiliations: Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada, Department of Physiology, University of Toronto, Toronto, Ontario, Canada

    Current address: Molecular, Cell & Developmental Biology, University of California Santa Cruz, 1156 High Street, Santa Cruz, CA 95064, United States of America.

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  • John R. Walker,

    Affiliation: Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada

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  • Valérie Campagna-Slater,

    Affiliation: Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada

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  • Patrick J. Finerty Jr,

    Affiliation: Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada

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  • Ragika Paramanathan,

    Affiliation: Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada

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  • Galina Bernstein,

    Affiliation: Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada

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  • Farrell MacKenzie,

    Affiliation: Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada

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  • Wolfram Tempel,

    Affiliation: Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada

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  • Hui Ouyang,

    Affiliation: Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada

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  • Wen Hwa Lee,

    Affiliations: Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada, University of Oxford, Headington, United Kingdom

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  • Elan Z. Eisenmesser,

    Affiliation: Department of Biochemistry & Molecular Genetics, University of Colorado Denver, Aurora, Colorado, United States of America

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  • Sirano Dhe-Paganon mail

    sirano.dhepaganon@utoronto.ca

    Affiliations: Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada, Department of Physiology, University of Toronto, Toronto, Ontario, Canada

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  • Published: July 27, 2010
  • DOI: 10.1371/journal.pbio.1000439
  • Published in PLOS Biology

Reader Comments (1)

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W121 role in substrate binding

Posted by p_carloni on 08 Feb 2011 at 16:15 GMT

Previous computational work with PPIA indicates that the function of Trp121 is mainly to serve to build a hydrophobic pocket for the substrate proline to insert (along with Phe60, Met61, Phe113, and Leu126) [55],[56]. However, our experimental data do not fully support this notion.
http://plosbiology.org/article/info:doi/10.1371/journal.pbio.1000439#article1.body1.sec2.sec1.p6

Davis et al. claim that there is an inconsistency between their measurements on W121 mutations and our conclusion, based on molecular simulation, that W121 plays a crucial role in substrate stabilization by hydrophobic interactions (Leone et al., PLoS Comput Biol 5: e1000309. doi:10.1371).

Specifically Davis et al. show that (i) the Trp121Tyr variant still retains isomerase activity, experimentally; (ii) the Trp121 forms an H-bond with a carbonyl of the cyclic undecapeptide cyclosporin A inhibitor, by modelling enzyme/inhibitor interaction. Then they extend this result to the substrate/enzyme interaction.

According to our calculations (Leone et al. PLoS Comput Biol 5: e1000309. doi:10.1371), W121 forms hydrophobic interactions with the Pro residue in the cyclophilin A/HAGPIA peptide complex, in substrate conformation, and hence is crucial for substrate binding.

We believe that this claim is not justified:

(i) Our conclusion is not inconsistent with the experimental finding that the Trp121Tyr variant still retains isomerase activity. Indeed, we expect that the tyrosine in the 121 position plays a similar role for substrate binding as Trp121, as both Tyr and Trp are aromatic residues.

(ii) Our conclusion is not inconsistent with the observations related to the binding of the cyclosporin A inhibitor. The inhibitor is a cyclic undecapeptide, hence structurally different from the HAGPIA peptide model substrate investigated by us. It is expected to be rather different also from the real substrate, a protein loop. Indeed, comparison of X-ray CypA/Ala-Pro peptide and CypA/cyclosporin A inhibitor shows a completely different H-bond network (Ke H, Mayrose D, Belshaw PJ, Alberg DG; Schreiber SL, Chang ZY, Etzkorn, FA 1994, Structure 2:33-44).

No competing interests declared.