Structural and functional characterization of the conserved salt bridge in mammalian paneth cell alpha-defensins: solution structures of mouse CRYPTDIN-4 and (E15D)-CRYPTDIN-4
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Structural and functional characterization of the conserved salt bridge in mammalian paneth cell alpha-defensins : solution structures of mouse CRYPTDIN-4 and (E15D)-CRYPTDIN-4. / Rosengren, K Johan; Daly, Norelle L; Fornander, Liselotte M; Jönsson, Linda M H; Shirafuji, Yoshinori; Qu, Xiaoqing; Vogel, Hans J; Ouellette, Andre J; Craik, David J; Kedström, Linda Maria Haugaard.
In: The Journal of Biological Chemistry, Vol. 281, No. 38, 22.09.2006, p. 28068-78.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Structural and functional characterization of the conserved salt bridge in mammalian paneth cell alpha-defensins
T2 - solution structures of mouse CRYPTDIN-4 and (E15D)-CRYPTDIN-4
AU - Rosengren, K Johan
AU - Daly, Norelle L
AU - Fornander, Liselotte M
AU - Jönsson, Linda M H
AU - Shirafuji, Yoshinori
AU - Qu, Xiaoqing
AU - Vogel, Hans J
AU - Ouellette, Andre J
AU - Craik, David J
AU - Kedström, Linda Maria Haugaard
PY - 2006/9/22
Y1 - 2006/9/22
N2 - 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.
AB - 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.
KW - Amino Acid Sequence
KW - Animals
KW - Anti-Infective Agents
KW - Humans
KW - Hydrogen-Ion Concentration
KW - Magnetic Resonance Spectroscopy
KW - Matrix Metalloproteinase 7
KW - Mice
KW - Molecular Sequence Data
KW - Mutation
KW - Rabbits
KW - Solutions
KW - Structure-Activity Relationship
KW - Temperature
KW - alpha-Defensins
U2 - 10.1074/jbc.M604992200
DO - 10.1074/jbc.M604992200
M3 - Journal article
C2 - 16857681
VL - 281
SP - 28068
EP - 28078
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 38
ER -
ID: 128007894