Ligand-induced dimer formation of calmodulin.
Calmodulin (CaM) can bind to numerous proteins in several interaction modes. Recently a new mode of interaction was discovered, in which two CaM molecules form an X-shaped dimer and two binding sites to trap the CaM-binding domain (CBD) of calcineurin subunit A. However, the X-shaped CaM dimer alone without ligand has not been observed. We performed molecular dynamics (MD) simulations and used MM_PBSA approach to investigate the properties of this new binding mode using ligand-bound and -free dimer systems. MD trajectories show that two peptides of CBD play a critical role in stabilizing the X-shaped conformation of the CaM dimer which would otherwise be unstable, leading to dimer disassembly in the absence of the ligands. Furthermore, we have analyzed the interaction free energy of the complex by MM-PBSA method and provide further evidence to demonstrate that the CBD peptide ligands are responsible for the stabilization of the dimer. Comparing this new binding mode with the classical one represented by CaM in complex with smooth muscle myosin light chain kinase, we conclude that this new binding mode is induced by the CBD of calcineurin subunit A. Our results explain the fact that the X-shaped CaM dimer structure has never been observed in the absence of ligands.
Zhang
Yong
Y
College of Chemistry, Beijing Normal University, Beijing 100875, People's Republic of China.
Tan
Hongwei
H
Jia
Zongchao
Z
Chen
Guangju
G
D001665:Binding Sites; D020013:Calcium Signaling; D002147:Calmodulin / Q000737:chemistry*; D002148:Calmodulin-Binding Proteins / Q000737:chemistry; D019281:Dimerization; D008024:Ligands; D008958:Models, Molecular; D020836:Protein Structure, Quaternary; D055672:Static Electricity; D013816:Thermodynamics
D002147:Calmodulin; D002148:Calmodulin-Binding Proteins; D008024:Ligands