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The activity of prolactin releasing peptide correlates with its helicity

Authors

  • Stephanie H. DeLuca,

    1. Vanderbilt University Center for Structural Biology, 5144B Biosci/MRBIII, 465 21st Avenue South, Nashville, TN 37232-8725
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  • Daniel Rathmann,

    1. Institute of Biochemistry, Faculty of Biosciences, Pharmacy and Psychology, Leipzig University, Brüderstraße 34, D-04103 Leipzig, Germany
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    • Stephanie H. DeLuca and Daniel Rathmann contributed equally to this work.

  • Annette G. Beck-Sickinger,

    Corresponding author
    1. Institute of Biochemistry, Faculty of Biosciences, Pharmacy and Psychology, Leipzig University, Brüderstraße 34, D-04103 Leipzig, Germany
    • Institute of Biochemistry, Faculty of Biosciences, Pharmacy and Psychology, Leipzig University, Brüderstraße 34, D-04103 Leipzig, Germany
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  • Jens Meiler

    Corresponding author
    1. Vanderbilt University Center for Structural Biology, 5144B Biosci/MRBIII, 465 21st Avenue South, Nashville, TN 37232-8725
    • Institute of Biochemistry, Faculty of Biosciences, Pharmacy and Psychology, Leipzig University, Brüderstraße 34, D-04103 Leipzig, Germany
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  • This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com

Abstract

The prolactin releasing peptide (PrRP) is involved in regulating food intake and body weight homeostasis, but molecular details on the activation of the PrRP receptor remain unclear. C-terminal segments of PrRP with 20 (PrRP20) and 13 (PrRP8-20) amino acids, respectively, have been suggested to be fully active. The data presented herein indicate this is true for the wildtype receptor only; a 5-10-fold loss of activity was found for PrRP8-20 compared to PrRP20 at two extracellular loop mutants of the receptor. To gain insight into the secondary structure of PrRP, we used CD spectroscopy performed in TFE and SDS. Additionally, previously reported NMR data, combined with ROSETTANMR, were employed to determine the structure of amidated PrRP20. The structural ensemble agrees with the spectroscopic data for the full-length peptide, which exists in an equilibrium between α- and 310-helix. We demonstrate that PrRP8-20's reduced propensity to form an α-helix correlates with its reduced biological activity on mutant receptors. Further, distinct amino acid replacements in PrRP significantly decrease affinity and activity but have no influence on the secondary structure of the peptide. We conclude that formation of a primarily α-helical C-terminal region of PrRP is critical for receptor activation. © 2012 Wiley Periodicals, Inc. Biopolymers 99: 273–281, 2013.

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