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Overexpression and Structural Study of the Cathelicidin Motif of the Protegrin-3 Precursor

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Download Hi-Res ImageDownload to MS-PowerPointCite This:Biochemistry 2002, 41, 1, 21-30
    Article

    Overexpression and Structural Study of the Cathelicidin Motif of the Protegrin-3 Precursor†
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    Centre de Biochimie Structurale, UMR 5048 CNRS-UM1/UMR 554 INSERM-UM1, Université Montpellier 1, Faculté de Pharmacie, 15 avenue Charles Flahault, 34093 Montpellier Cedex 5, France, Laboratoire de Spectrométrie de Masse Bio-Organique, ECPM, 25, rue Becquerel, 67087, Strasbourg Cedex 2, France, Université Montpellier II, CNRS UMR 5539, CC 107, 34095 Montpellier Cedex 05, France, and Department of Medicine, Center for the Health Sciences, Los Angeles, California 90095
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    Biochemistry

    Cite this: Biochemistry 2002, 41, 1, 21–30
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    https://doi.org/10.1021/bi010930a
    Published December 7, 2001
    Copyright © 2002 American Chemical Society
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    Abstract

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    Numerous precursors of antibacterial peptides with unrelated sequences share a similar prosequence of 96−101 residues, referred to as the cathelicidin motif. The structure of this widespread motif has not yet been reported. The cathelicidin motif of protegrin-3 (ProS) was overexpressed in Escherichia coli as a His-tagged protein to facilitate its purification. The His tag was then removed by thrombin cleavage. In addition, the complete proprotegrin-3 (ProS-PG-3) (120 residues) was overexpressed in baculovirus-infected insect cells. As it contained the antibacterial peptide protegrin-3 in its C-terminal part, ProS-PG-3 contained four disulfide bonds. At neutral pH, ProS and ProS-PG-3 adopted two slowly exchanging conformations that existed in a ratio of 55/45. This ratio was progressively modified at acidic pH to reach a 90/10 value at pH 3.0, suggesting that electrostatic interactions are involved in such a conformational change. Therefore, the structural study of the main conformer was undertaken at pH 3.0 by circular dichroism, mass spectrometry, and homo- and heteronuclear NMR. In parallel, a model for the ProS structure was built from the X-ray structure of the chicken cystatin. ProS and the chicken cystatin share two conserved disulfide bonds as well as a high conservation of hydrophobic residues. The ProS model features the conservation of a hydrophobic core made of the interface between the N-terminal helix and the wrapping β-sheet. Although the full assignment of the main conformer of ProS could not be obtained, available NMR data validated the presence of the N-terminal helix and of a four-stranded β-sheet, in agreement with the cystatin fold. Moreover, we clearly demonstrated that ProS and ProS-PG-3 share the same global structure, suggesting that the presence of the highly constrained β-hairpin of protegrin does not significantly modify the structure of the cathelicidin motif of the protegrin precursor.

    Copyright © 2002 American Chemical Society

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    †

     This research was supported by a grant from the Ministère de l'Education Nationale, de la Recherche, et de la Technologie (J.F.S.).

    ‡

     Centre de Biochimie Structurale.

    §

     Laboratoire de Spectrométrie de Masse Bio-Organique.

    ‖

     Université Montpellier II.

    ⊥

     Center for the Health Sciences.

    *

     To whom correspondence should be addressed. Tel:  33 467 043 432. Fax:  33 467 529 623. E-mail:  [email protected].

    Supporting Information Available

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    Figure S1 showing slices of the NOESY-HSQC 3D experiment recorded at pH 3.0 showing the dNN NOEs of the N-terminal part and Figures S2 and S3 showing the 1H−15N HSQC spectrum of ProS recorded at pH 7.0 (37 °C) and pH 3.0 (37 °C), respectively. This material is available free of charge via the Internet at http://pubs.acs.org.

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    Cited By

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    This article is cited by 17 publications.

    1. Marzena Pazgier, Bryan Ericksen, Minhua Ling, Eric Toth, Jishu Shi, Xiangdong Li, Amy Galliher-Beckley, Liqiong Lan, Guozhang Zou, Changyou Zhan, Weirong Yuan, Edwin Pozharski, and Wuyuan Lu . Structural and Functional Analysis of the Pro-Domain of Human Cathelicidin, LL-37. Biochemistry 2013, 52 (9) , 1547-1558. https://doi.org/10.1021/bi301008r
    2. Yaying Zhang, Chunyang Cao. NMR assisted studies on the solution structures and functions of antimicrobial peptides. Magnetic Resonance Letters 2022, 2 (4) , 214-223. https://doi.org/10.1016/j.mrl.2022.08.001
    3. Yiyun Zhu, Weijing Hao, Xia Wang, Jianhong Ouyang, Xinyi Deng, Haining Yu, Yipeng Wang. Antimicrobial peptides, conventional antibiotics, and their synergistic utility for the treatment of drug‐resistant infections. Medicinal Research Reviews 2022, 42 (4) , 1377-1422. https://doi.org/10.1002/med.21879
    4. Lingman Ma, Yanrong Wang, Mengxiao Wang, Yuwei Tian, Wei Kang, Hanhan Liu, Hui Wang, Jie Dou, Changlin Zhou. Effective antimicrobial activity of Cbf-14, derived from a cathelin-like domain, against penicillin-resistant bacteria. Biomaterials 2016, 87 , 32-45. https://doi.org/10.1016/j.biomaterials.2016.02.011
    5. Daniela Xhindoli, Sabrina Pacor, Monica Benincasa, Marco Scocchi, Renato Gennaro, Alessandro Tossi. The human cathelicidin LL-37 — A pore-forming antibacterial peptide and host-cell modulator. Biochimica et Biophysica Acta (BBA) - Biomembranes 2016, 1858 (3) , 546-566. https://doi.org/10.1016/j.bbamem.2015.11.003
    6. Hui-Juan GUANG, Zheng LI, Yi-Peng WANG, Ren LAI, Hai-Ning YU. Progress in cathelicidins antimicrobial peptides research. Zoological Research 2013, 33 (5) , 523-526. https://doi.org/10.3724/SP.J.1141.2012.05523
    7. Mercedes Leonor Sánchez, Melina María Belén Martínez, Paulo César Maffia. Natural Antimicrobial Peptides: Pleiotropic Molecules in Host Defense. CellBio 2013, 02 (04) , 200-210. https://doi.org/10.4236/cellbio.2013.24023
    8. Robert I. Lehrer, Tomas Ganz. Antimicrobial Peptides: Defensins and Cathelicidins. 2010https://doi.org/10.1002/9780470688618.taw0091
    9. Yuping Lai, Richard L. Gallo. AMPed up immunity: how antimicrobial peptides have multiple roles in immune defense. Trends in Immunology 2009, 30 (3) , 131-141. https://doi.org/10.1016/j.it.2008.12.003
    10. Shunyi Zhu, Liang Wei, Kenshi Yamasaki, Richard L. Gallo. Activation of cathepsin L by the cathelin-like domain of protegrin-3. Molecular Immunology 2008, 45 (9) , 2531-2536. https://doi.org/10.1016/j.molimm.2008.01.007
    11. Botond Penke, Gábor Tóth, Györgyi Váradi. Analogue and Conformational Studies on Peptides, Hormones and Other Biologically Active Peptides. 2006, 129-271. https://doi.org/10.1039/9781847555250-00129
    12. Susan E. Sweeney, Yoon B. Kim. Identification of a Novel FcγRIIIaα-Associated Molecule That Contains Significant Homology to Porcine Cathelin. The Journal of Immunology 2004, 172 (2) , 1203-1212. https://doi.org/10.4049/jimmunol.172.2.1203
    13. Ann Eisenberg Shinnar, Kathryn L. Butler, Hyon Ju Park. Cathelicidin family of antimicrobial peptides: proteolytic processing and protease resistance. Bioorganic Chemistry 2003, 31 (6) , 425-436. https://doi.org/10.1016/S0045-2068(03)00080-4
    14. Marie-Paule Strub, François Hoh, Jean-Frédéric Sanchez, Jean Marc Strub, August Böck, André Aumelas, Christian Dumas. Selenomethionine and Selenocysteine Double Labeling Strategy for Crystallographic Phasing. Structure 2003, 11 (11) , 1359-1367. https://doi.org/10.1016/j.str.2003.09.014
    15. Mohamed Zaiou, Victor Nizet, Richard L. Gallo. Antimicrobial and Protease Inhibitory Functions of the Human Cathelicidin (hCAP18/LL-37) Prosequence. Journal of Investigative Dermatology 2003, 120 (5) , 810-816. https://doi.org/10.1046/j.1523-1747.2003.12132.x
    16. Yinshan Yang, Jean Frédéric Sanchez, Marie-Paule Strub, Bernhard Brutscher, André Aumelas. NMR Structure of the Cathelin-like Domain of the Protegrin-3 Precursor. Biochemistry 2003, 42 (16) , 4669-4680. https://doi.org/10.1021/bi027133c
    17. Jean-Frédéric Sanchez, François Hoh, Marie-Paule Strub, André Aumelas, Christian Dumas. Structure of the Cathelicidin Motif of Protegrin-3 Precursor. Structure 2002, 10 (10) , 1363-1370. https://doi.org/10.1016/S0969-2126(02)00859-6
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    Biochemistry

    Cite this: Biochemistry 2002, 41, 1, 21–30
    Click to copy citationCitation copied!
    https://doi.org/10.1021/bi010930a
    Published December 7, 2001
    Copyright © 2002 American Chemical Society
    Request reuse permissions

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