title: R102Q mutation shifts the salt-bridge network and reduces the structural flexibility of human neuronal calcium sensor-1 protein.
abstract: Neuronal calcium sensor-1 (NCS-1) protein has a variety of different neuronal functions and interacts with multiple binding partners mostly through a large solvent-exposed hydrophobic crevice (HC). A single R102Q mutation in human NCS-1 protein was demonstrated to be associated with autism disease. Solution NMR study reported that this R102Q mutant had long-range chemical shift effects on the HC and the C-terminal tail (L3). To understand the influence of the R102Q mutation on the HC and L3 of NCS-1, we have investigated the conformational dynamics and the structural flexibility of wild type (WT) NCS-1 and its R102Q mutant by conducting extensive all-atom molecular dynamics (MD) simulations. On the basis of six independent 450 ns MD simulations, we have found that the R102Q mutation in NCS-1 protein (1) dramatically reduces the flexibility of loops L2 and L3, (2) facilitates L3 in a more extended state to occupy the hydrophobic crevice to a larger extent, (3) significantly affects the intersegment salt bridges, and (4) changes the subspace of the free energy landscape of NCS-1 protein. Analysis of the salt bridge network in both WT and the R102Q variant demonstrates that the R102Q-mutation-induced salt bridge alternations play a critical role on the reduced flexibility of L2 and L3. These results reveal the important role of salt bridges on the structural properties of NCS-1 protein and that R102Q mutation disables the dynamic relocation of C-terminus, which may block the binding of NCS-1 protein to its receptors. This study may provide structural insights into the autistic spectrum disorder associated with R102Q mutation.
authors.affiliation: College of Physical Education & Training, Shanghai University of Sport , 399 Chang Hai Road, Shanghai, 200438, China.
authors.forename: Yuzhen
authors.initials: Y
authors.lastname: Zhu
authors.forename: Ying
authors.initials: Y
authors.lastname: Wu
authors.forename: Yin
authors.initials: Y
authors.lastname: Luo
authors.forename: Yu
authors.initials: Y
authors.lastname: Zou
authors.forename: Buyong
authors.initials: B
authors.lastname: Ma
authors.forename: Qingwen
authors.initials: Q
authors.lastname: Zhang
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D051580:Neuronal Calcium-Sensor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009479:Neuropeptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D019906:Nuclear Magnetic Resonance, Biomolecular; D017434:Protein Structure, Tertiary; D012492:Salts / Q000737:chemistry; D013816:Thermodynamics
chemical_list: D051580:Neuronal Calcium-Sensor Proteins; D009479:Neuropeptides; D012492:Salts; C101464:frequenin calcium sensor proteins