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The alpha-defensin salt-bridge induces backbone stability to facilitate folding and confer proteolytic resistance
Linnéuniversitetet, Fakultetsnämnden för naturvetenskap och teknik, Institutionen för naturvetenskap, NV. (BBCL)ORCID-id: 0000-0003-1241-8888
Linnéuniversitetet, Fakultetsnämnden för naturvetenskap och teknik, Institutionen för naturvetenskap, NV.
Linnéuniversitetet, Fakultetsnämnden för naturvetenskap och teknik, Institutionen för naturvetenskap, NV.
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2012 (engelsk)Inngår i: Amino Acids, ISSN 0939-4451, E-ISSN 1438-2199, Vol. 43, nr 4, s. 1471-1483Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

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.

sted, utgiver, år, opplag, sider
2012. Vol. 43, nr 4, s. 1471-1483
Emneord [en]
Defensin, Cryptdin-4, Crp4, Salt-bridge, Structure, Folding, Proteolytic stability
HSV kategori
Forskningsprogram
Kemi, Biokemi; Kemi, Organisk kemi
Identifikatorer
URN: urn:nbn:se:lnu:diva-22288DOI: 10.1007/s00726-012-1220-3ISI: 000309070700007Scopus ID: 2-s2.0-84867577474OAI: oai:DiVA.org:lnu-22288DiVA, id: diva2:565152
Tilgjengelig fra: 2012-11-06 Laget: 2012-11-06 Sist oppdatert: 2017-04-18bibliografisk kontrollert

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