Structure of G57W mutant of human γS-crystallin and its involvement in cataract formation |
| |
Authors: | Khandekar Jishan Bari Shrikant Sharma Kandala VR Chary |
| |
Institution: | 1. Center for Interdisciplinary Sciences, Tata Institute of Fundamental Research, Gopanpally, Hyderabad 500107, India;2. Department of Chemical Sciences, Tata Institute of Fundamental Research, 1, Homi Bhabha Road, Colaba, Mumbai 400005, India;3. Indian Institute of Science Education and Research, Berhampur, Odisha 760010, India |
| |
Abstract: | A recently identified mutant of human γS-crystallin, G57W is associated with dominant congenital cataracts, the familial determinate of childhood blindness worldwide. To investigate the structural and functional changes that mediate the effect of this cataract-related mutant to compromise eye lens transparency and cause lens opacification in children, we recently reported complete sequence-specific resonance assignments of γS-G57W using a suite of heteronuclear NMR experiments. As a follow up, we have determined the 3D structure of γS-G57W and studied its conformational dynamics by solution NMR spectroscopy. Our structural dynamics results reveal greater flexibility of the N-terminal domain, which undergoes site-specific structural changes to accommodate W57, than its C-terminal counterpart. Our structural inferences that the unusual solvent exposure of W57 is associated with rearrangement of the N-terminal domain suggest an efficient pathway for increased aggregation in γS-G57W and illuminates the molecular dynamics underlying cataractogenic aggregation of lens crystallins in particular and aggregation of proteins in general. |
| |
Keywords: | Congenital cataract 3D structure Conformational dynamics Aggregation propensity |
本文献已被 ScienceDirect 等数据库收录! |
|