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The alpha-defensin ...
The alpha-defensin salt-bridge induces backbone stability to facilitate folding and confer proteolytic resistance
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- Andersson, Håkan S. (author)
- Linnéuniversitetet,Institutionen för naturvetenskap, NV,BBCL
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Figueredo, Sharel M. (author)
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- Haugaard-Kedström, Linda M. (author)
- Linnéuniversitetet,Institutionen för naturvetenskap, NV
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- Bengtsson, Elina (author)
- Linnéuniversitetet,Institutionen för naturvetenskap, NV
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Daly, Norelle L. (author)
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Qu, Xiaoqing (author)
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Craik, David J. (author)
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Ouellette, Andre J. (author)
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- Rosengren, K. Johan (author)
- Linnéuniversitetet,Institutionen för naturvetenskap, NV
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(creator_code:org_t)
- 2012-01-29
- 2012
- English.
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In: Amino Acids. - : Springer Science and Business Media LLC. - 0939-4451 .- 1438-2199. ; 43:4, s. 1471-1483
- Related links:
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https://europepmc.or...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Subject headings
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- Salt-bridge interactions between acidic and basic amino acids contribute to the structural stability of proteins and to protein-protein interactions. A conserved salt-bridge is a canonical feature of the alpha-defensin antimicrobial peptide family, but the role of this common structural element has not been fully elucidated. We have investigated mouse Paneth cell alpha-defensin cryptdin-4 (Crp4) and peptide variants with mutations at Arg(7) or Glu(15) residue positions to disrupt the salt-bridge and assess the consequences on Crp4 structure, function, and stability. NMR analyses showed that both (R7G)-Crp4 and (E15G)-Crp4 adopt native-like structures, evidence of fold plasticity that allows peptides to reshuffle side chains and stabilize the structure in the absence of the salt-bridge. In contrast, introduction of a large hydrophobic side chain at position 15, as in (E15L)-Crp4 cannot be accommodated in the context of the Crp4 primary structure. Regardless of which side of the salt-bridge was mutated, salt-bridge variants retained bactericidal peptide activity with differential microbicidal effects against certain bacterial cell targets, confirming that the salt-bridge does not determine bactericidal activity per se. The increased structural flexibility induced by salt-bridge disruption enhanced peptide sensitivity to proteolysis. Although sensitivity to proteolysis by MMP7 was unaffected by most Arg(7) and Glu(15) substitutions, every salt-bridge variant was degraded extensively by trypsin. Moreover, the salt-bridge facilitates adoption of the characteristic alpha-defensin fold as shown by the impaired in vitro refolding of (E15D)-proCrp4, the most conservative salt-bridge disrupting replacement. In Crp4, therefore, the canonical alpha-defensin salt-bridge facilitates adoption of the characteristic alpha-defensin fold, which decreases structural flexibility and confers resistance to degradation by proteinases.
Subject headings
- NATURVETENSKAP -- Kemi -- Organisk kemi (hsv//swe)
- NATURAL SCIENCES -- Chemical Sciences -- Organic Chemistry (hsv//eng)
Keyword
- Defensin
- Cryptdin-4
- Crp4
- Salt-bridge
- Structure
- Folding
- Proteolytic stability
- Biochemistry
- Biokemi
- Organisk kemi
- Organic Chemistry
Publication and Content Type
- ref (subject category)
- art (subject category)
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