Rosengren, K Johan2; Daly, Norelle L3; Fornander, Liselotte M3; Jönsson, Linda M H3; Shirafuji, Yoshinori3; Qu, Xiaoqing3; Vogel, Hans J3; Ouellette, Andre J3; Craik, David J3; Kedström, Linda Maria Haugaard4
1 Medicinal Chemistry Research, Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, Københavns Universitet2 Department of Chemistry and Biomedical Sciences, University of Kalmar, SE-391 82 Kalmar, Sweden. firstname.lastname@example.org unknown4 Medicinal Chemistry Research, Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, Københavns Universitet
solution structures of mouse CRYPTDIN-4 and (E15D)-CRYPTDIN-4
alpha-Defensins are mediators of mammalian innate immunity, and knowledge of their structure-function relationships is essential for understanding their mechanisms of action. We report here the NMR solution structures of the mouse Paneth cell alpha-defensin cryptdin-4 (Crp4) and a mutant (E15D)-Crp4 peptide, in which a conserved Glu(15) residue was replaced by Asp. Structural analysis of the two peptides confirms the involvement of this Glu in a conserved salt bridge that is removed in the mutant because of the shortened side chain. Despite disruption of this structural feature, the peptide variant retains a well defined native fold because of a rearrangement of side chains, which result in compensating favorable interactions. Furthermore, salt bridge-deficient Crp4 mutants were tested for bactericidal effects and resistance to proteolytic degradation, and all of the variants had similar bactericidal activities and stability to proteolysis. These findings support the conclusion that the function of the conserved salt bridge in Crp4 is not linked to bactericidal activity or proteolytic stability of the mature peptide.
Journal of Biological Chemistry, 2006, Vol 281, Issue 38, p. 28068-78