期刊
JOURNAL OF MOLECULAR GRAPHICS & MODELLING
卷 24, 期 3, 页码 175-185出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jmgm.2005.07.003
关键词
plasma membrane Ca2+-ATPase; calmodulin; PMCA; oxidation; homology modeling; threading; molecular dynamics
类别
资金
- NCRR NIH HHS [RR017708] Funding Source: Medline
- NIA NIH HHS [AG12993] Funding Source: Medline
Oxidative damage to the plasma membrane Ca2+-ATPase (PMCA) appears to contribute to the decreased clearance of intracellular Ca2+ in the neurons of aged brain, possibly contributing to its vulnerability to numerous age-related diseases such as Alzheimer's disease. The precise sites of oxidative susceptibility have not been identified. However, it is known that calmodulin (CaM) protects the purified PMCA against oxidative inactivation, perhaps via conformational restructuring of the protein through dissociation of a 20 residue domain (C20W) in the C-terminal region that function as a CaM-binding site. In order to postulate likely oxidation sites and the mechanism underlying the protection offered by CaM, we have generated a three-dimensional model of PMCA via a combination of homology/comparative modeling, threading, protein-protein docking, and guidance from prior biochemical and analytical studies. The resulting model was validated based on surface polarity/hydrophobicity profiling, standard ProCheck, WhatIF. and PROVE checks, as well as comparison with empirical structure-function observations. This model was then used to identify likely oxidation sites by comparing time-averaged solvent accessibility of potentially oxidizable surface residues as measured from molecular dynamics simulations of intact PMCA and the PMCA sequence from which C20W has been deleted. The resulting model complex has permitted us to identify three amino acids whose solvent accessibility is greatly reduced by the C20W dissociation: Tyr589, Met622, and Met831. (C) 2005 Elsevier Inc. All rights reserved.
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