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. 2018 Oct 20;505(1):236-241.
doi: 10.1016/j.bbrc.2018.09.052. Epub 2018 Sep 20.

Unique Methionine-Aromatic Interactions Govern the Calmodulin Redox Sensor

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Free PMC article

Unique Methionine-Aromatic Interactions Govern the Calmodulin Redox Sensor

Daniel G Walgenbach et al. Biochem Biophys Res Commun. .
Free PMC article

Abstract

Calmodulin contains multiple redox sensitive methionines whose oxidation alters the regulation of numerous targets. Molecular dynamics simulations were used to define the molecular principles that govern how calmodulin is structurally poised to detect and respond to methionine oxidation. We found that calmodulin's open and closed states were preferentially stabilized by unique, redox sensitive, methionine-aromatic interactions. Key methionine-aromatic interactions were coupled to reorientation of EF hand helices. Methionine to glutamine substitutions designed to mimic methionine oxidation strongly altered conformational transitions by modulating the strength of methionine-aromatic interactions. Together, these results suggest a broadly applicable redox sensing mechanism though which methionine oxidation by cellular oxidants alters the strength of methionine-aromatic interactions critical for functional protein dynamics.

Keywords: Aging; Calmodulin; Methionine; Oxidation.

Figures

Fig. 1:
Fig. 1:
A. Methionine can be oxidized to methionine sulfoxide by oxidants; glutamine substitution mimics methionine sulfoxide. B: Geometry of the methionine-aromatic interaction. C: Structural models of calmodulin’s open (PDB: 1CLL) and closed (PDB: 1CFD) states.
Fig. 2:
Fig. 2:
Time-averaged structural measurements for the closed (1CFD, black) and open (1CLL, red) structural states over the course of one microsecond simulations. A: Distribution of distances between Cα’s of T34 and T117. B: Methionine SASA. C: Per residue RMSF. D: Secondary structure.
Fig. 3:
Fig. 3:
Specific Met-aromatic interactions stabilize the open and closed states.
Fig. 4:
Fig. 4:
A. Normal modes extracted from WT apo1CLL trajectories captured correlated motions during key conformational transitions. B: Events accompanying the open to closed structural transition for WT CaM and mutants

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