NDLI: The α-defensin salt-bridge induces backbone stability to facilitate folding and confer proteolytic resistance

Content Provider	Springer Nature Link
Author	Andersson, Håkan S. Figueredo, Sharel M. Haugaard Kedström, Linda M. Bengtsson, Elina Daly, relle L. Qu, Xiaoqing Craik, David J. Ouellette, André J. Rosengren, K. Johan
Copyright Year	2012
Abstract	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 α-defensin antimicrobial peptide family, but the role of this common structural element has not been fully elucidated. We have investigated mouse Paneth cell α-defensin cryptdin-4 (Crp4) and peptide variants with mutations at Arg7 or Glu15 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 Arg7 and Glu15 substitutions, every salt-bridge variant was degraded extensively by trypsin. Moreover, the salt-bridge facilitates adoption of the characteristic α-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 α-defensin salt-bridge facilitates adoption of the characteristic α-defensin fold, which decreases structural flexibility and confers resistance to degradation by proteinases.
Starting Page	1471
Ending Page	1483
Page Count	13
File Format	PDF
ISSN	09394451
Journal	Amino Acids
Volume Number	43
Issue Number	4
e-ISSN	14382199
Language	English
Publisher	Springer Vienna
Publisher Date	2012-01-29
Publisher Place	Vienna
Access Restriction	Subscribed
Subject Keyword	Defensin Cryptdin-4 Crp4 Salt-bridge Structure Folding Proteolytic stability Proteomics Life Sciences Neurobiology Biochemistry Biochemical Engineering Analytical Chemistry
Content Type	Text
Resource Type	Article
Subject	Organic Chemistry Biochemistry Clinical Biochemistry

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