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Inhibition of semen-derived enhancer of virus infection (SEVI) fibrillogenesis by zinc and copper

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Abstract

Semen-derived enhancer of virus infection (SEVI), a naturally occurring peptide fragment of prostatic acid phosphatase, enhances HIV infectivity by forming cationic amyloid fibrils that aid the fusion of negatively charged virion and target cell membranes. Cu(II) and Zn(II) inhibit fibrillization of SEVI in a kinetic assay using the fibril-specific dye ThT. TEM suggests that the metals do not affect fibril morphology. NMR shows that the metals bind to histidines 3 and 23 in the SEVI sequence. ITC experiments indicate that SEVI forms oligomeric complexes with the metals. Dissociation constants are micromolar for Cu(II) and millimolar for Zn(II). Because the Cu(II) and Zn(II) concentrations that inhibit fibrillization are comparable with those found in seminal fluid the metals may modulate SEVI fibrillization under physiological conditions.

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Abbreviations

DMSO:

Dimethyl sulfoxide

EDTA:

Ethylenediaminetetraacetic acid

ITC:

Isothermal titration calorimetry

HIV:

Human immunodeficiency virus

HSQC:

Heteronuclear single-quantum coherence

NMR:

Nuclear magnetic resonance

NOESY:

Nuclear Overhauser enhancement spectroscopy

PBS:

Phosphate-buffered saline

TBS:

Tris-buffered saline

TEM:

Transmission electron microscopy

ThT:

Thioflavin T

TOCSY:

Total correlation spectroscopy

SEVI:

Semen-derived enhancer of virus infection—in this case, specifically the 248–286 fragment of human prostatic acid phosphatase: PAP248–286

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Acknowledgments

We thank Molly Siegel and Tyler Daman for technical assistance during the early stages of this project and Dr Olga Vinogradova for use of her ITC machine. This work was supported by an NSF Graduate Research Fellowship to SRS, a UConn Summer Undergraduate Research Fellowship to JS, and by an American Diabetes Association Basic Science Award to ATA.

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Authors and Affiliations

  1. Department of Molecular and Cell Biology, University of Connecticut, 91 N. Eagleville Rd., Storrs, CT, 06269-3125, USA

    Sarah R. Sheftic, Jessica M. Snell, Suman Jha & Andrei T. Alexandrescu

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  1. Sarah R. Sheftic
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  2. Jessica M. Snell
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  3. Suman Jha
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  4. Andrei T. Alexandrescu
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Correspondence to Andrei T. Alexandrescu.

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The authors Sarah R. Sheftic and Jessica M. Snell contributed equally to this work.

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Sheftic, S.R., Snell, J.M., Jha, S. et al. Inhibition of semen-derived enhancer of virus infection (SEVI) fibrillogenesis by zinc and copper. Eur Biophys J 41, 695–704 (2012). https://doi.org/10.1007/s00249-012-0846-0

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  • DOI: https://doi.org/10.1007/s00249-012-0846-0

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