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Reconstruction of the Conserved β-Bulge in Mammalian Defensins Using D-Amino Acids.

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Title: Reconstruction of the Conserved β-Bulge in Mammalian Defensins Using D-Amino Acids.
Authors: Cao Xie1,2, Prahl, Adam3, Ericksen, Bryan1, Zhibin Wu1, Pengyun Zeng2, Xiangqun Li1, Wei-Yue Lu2, Lubkowski, Jacek3 jacek@ncifcrf.gov, Wuyuan Lu1 luw@umbi.umd.edu
Source: Journal of Biological Chemistry. 9/23/2005, Vol. 280 Issue 38, p32921-32929. 9p. 4 Diagrams, 2 Charts, 7 Graphs.
Subjects: Proteins, Amino acids, Immune system, Enantiomers, Neutrophils, Dimers
Abstract: Defensins are cationic antimicrobial mini-proteins that play important roles in the innate immune defense against microbial infection. Six invariant Cys residues in each defensin form three structurally indispensable intramolecular disulfide bridges. The only other residue invariant in all known mammalian defensins is a Gly. Structural studies indicate that the invariant Gly residue is located in an atypical, classic-type β-bulge with the backbone torsion angles (ϕ, ψ) disallowed for L-amino acids but permissible for D-enantiomers. We replaced the invariant Gly17 residue in human neutrophil α-defensin 2 (HNP2) by L-Ala or one of the D-amino acids Ala, Glu, Phe, Arg, Thr, Val, or Tyr. Although L-Ala17-HNP2 could not be folded, resulting in massive aggregation, all of the D-amino acid-substituted analogs folded with high efficiency. The high resolution x-ray crystal structures of dimeric D-Ala17-HNP2 were determined in three different crystal forms, showing a well preserved β-bulge identical to those found in other defensins. The seven D-analogs of HNP2 exhibited highly variable bactericidal activity against Gram-positive and Gram-negative test strains, consistent with the premise that interplay between charge and hydrophobicity dictates how amphiphilic defensins kill. Further, the bactericidal activity of these D-amino acid analogs of HNP2 correlated well with their ability to induce leakage from large unilamellar vesicles, supporting membrane permeabilization as the lethal event in microbial killing by HNP2. Our findings identify a conformational prerequisite in the β-bulge of defensins essential for correct folding and native structure, thereby explaining the molecular basis of the Gly-Xaa-Cys motif conserved in all mammalian defensins. [ABSTRACT FROM AUTHOR]
Copyright of Journal of Biological Chemistry is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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DbLabel: Engineering Source
An: 18452311
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PubTypeId: academicJournal
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  Data: Reconstruction of the Conserved β-Bulge in Mammalian Defensins Using D-Amino Acids.
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  Data: <searchLink fieldCode="AR" term="%22Cao+Xie%22">Cao Xie</searchLink><relatesTo>1,2</relatesTo><br /><searchLink fieldCode="AR" term="%22Prahl%2C+Adam%22">Prahl, Adam</searchLink><relatesTo>3</relatesTo><br /><searchLink fieldCode="AR" term="%22Ericksen%2C+Bryan%22">Ericksen, Bryan</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Zhibin+Wu%22">Zhibin Wu</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Pengyun+Zeng%22">Pengyun Zeng</searchLink><relatesTo>2</relatesTo><br /><searchLink fieldCode="AR" term="%22Xiangqun+Li%22">Xiangqun Li</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Wei-Yue+Lu%22">Wei-Yue Lu</searchLink><relatesTo>2</relatesTo><br /><searchLink fieldCode="AR" term="%22Lubkowski%2C+Jacek%22">Lubkowski, Jacek</searchLink><relatesTo>3</relatesTo><i> jacek@ncifcrf.gov</i><br /><searchLink fieldCode="AR" term="%22Wuyuan+Lu%22">Wuyuan Lu</searchLink><relatesTo>1</relatesTo><i> luw@umbi.umd.edu</i>
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  Data: <searchLink fieldCode="JN" term="%22Journal+of+Biological+Chemistry%22">Journal of Biological Chemistry</searchLink>. 9/23/2005, Vol. 280 Issue 38, p32921-32929. 9p. 4 Diagrams, 2 Charts, 7 Graphs.
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  Data: <searchLink fieldCode="DE" term="%22Proteins%22">Proteins</searchLink><br /><searchLink fieldCode="DE" term="%22Amino+acids%22">Amino acids</searchLink><br /><searchLink fieldCode="DE" term="%22Immune+system%22">Immune system</searchLink><br /><searchLink fieldCode="DE" term="%22Enantiomers%22">Enantiomers</searchLink><br /><searchLink fieldCode="DE" term="%22Neutrophils%22">Neutrophils</searchLink><br /><searchLink fieldCode="DE" term="%22Dimers%22">Dimers</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: Defensins are cationic antimicrobial mini-proteins that play important roles in the innate immune defense against microbial infection. Six invariant Cys residues in each defensin form three structurally indispensable intramolecular disulfide bridges. The only other residue invariant in all known mammalian defensins is a Gly. Structural studies indicate that the invariant Gly residue is located in an atypical, classic-type β-bulge with the backbone torsion angles (ϕ, ψ) disallowed for L-amino acids but permissible for D-enantiomers. We replaced the invariant Gly17 residue in human neutrophil α-defensin 2 (HNP2) by L-Ala or one of the D-amino acids Ala, Glu, Phe, Arg, Thr, Val, or Tyr. Although L-Ala17-HNP2 could not be folded, resulting in massive aggregation, all of the D-amino acid-substituted analogs folded with high efficiency. The high resolution x-ray crystal structures of dimeric D-Ala17-HNP2 were determined in three different crystal forms, showing a well preserved β-bulge identical to those found in other defensins. The seven D-analogs of HNP2 exhibited highly variable bactericidal activity against Gram-positive and Gram-negative test strains, consistent with the premise that interplay between charge and hydrophobicity dictates how amphiphilic defensins kill. Further, the bactericidal activity of these D-amino acid analogs of HNP2 correlated well with their ability to induce leakage from large unilamellar vesicles, supporting membrane permeabilization as the lethal event in microbial killing by HNP2. Our findings identify a conformational prerequisite in the β-bulge of defensins essential for correct folding and native structure, thereby explaining the molecular basis of the Gly-Xaa-Cys motif conserved in all mammalian defensins. [ABSTRACT FROM AUTHOR]
– Name: AbstractSuppliedCopyright
  Label:
  Group: Ab
  Data: <i>Copyright of Journal of Biological Chemistry is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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      – Type: doi
        Value: 10.1074/jbc.M503084200
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      – Code: eng
        Text: English
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      Pagination:
        PageCount: 9
        StartPage: 32921
    Subjects:
      – SubjectFull: Proteins
        Type: general
      – SubjectFull: Amino acids
        Type: general
      – SubjectFull: Immune system
        Type: general
      – SubjectFull: Enantiomers
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      – SubjectFull: Neutrophils
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      – SubjectFull: Dimers
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      – TitleFull: Reconstruction of the Conserved β-Bulge in Mammalian Defensins Using D-Amino Acids.
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            NameFull: Cao Xie
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              M: 09
              Text: 9/23/2005
              Type: published
              Y: 2005
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