Paper Citing NAMD - Abstract
Xi, Yi-Bo; Zhao, Wei-Jie; Zuo, Xiao-Tong; Tjondro, Harry Christianto; Li, Jing; Dai, An-Bang; Wang, Sha; Yan, Yong-Bin
Cataract-causing mutation R233H affects the stabilities of beta B1-and beta A3/beta B1-crystallins with different pH-dependence
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE, 1842:2216-2229, NOV 2014
Disease-causing mutations can be stabilizing or destabilizing. Missense mutations of structural residues are generally destabilizing, while stabilizing mutations are usually linked to alterations in protein functions. Stabilizing mutations are rarely identified in mutations linked to congenital cataract, a disease caused by the opacification of the lens. In this research, we found that R233H mutation had little impact on beta B1-crystallin structure, solubility and thermal stability under neutral solution pH conditions. The mutation increased beta B1 stability against guanidine hydrochloride-induced denaturation, suggesting that Arg233 might be a functional residue. Further analysis indicated that the R233H mutation did not affect the formation of beta A3/beta B1 heteromer, but significantly reduced heteromer stability against heat- and guanidine hydrochloride-induced denaturation. The R233H mutation negatively affected the thermal stabilities and aggregatory propensities of psi and beta A3/beta B1 with different pH-dependence, implying that the protonation of His side chains during acidification played a regulatory role in crystallin stability and aggregation. Molecular dynamic simulations indicated that Arg233 is one of the residues forming an inter-subunit ion-pairing network with intrinsically dynamic nature. Based on these observations, we proposed that the highly dynamic ion-pairing network contributed to the tradeoff among beta B1 solubility, stability, aggregatory propensity and function of protecting beta A3. (C) 2014 Elsevier B.V. All rights reserved.
