TITLE

The Mutation V42M Distorts the Compact Packing of the Human Gamma-S-Crystallin Molecule, Resulting in Congenital Cataract

AUTHOR(S)
Rao Vendra, Venkata Pulla; Chandani, Sushil; Balasubramanian, Dorairajan
PUB. DATE
December 2012
SOURCE
PLoS ONE;Dec2012, Vol. 7 Issue 12, p1
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
Background: Human γS-crystallin is an important component of the human eye lens nucleus and cortex. The mutation V42M in the molecule causes severe congenital cataract in children. We compare the structure of the mutant protein with that of the wild type in order to understand how structural changes in the mutant relate to the mechanism of opacification. Methods: Both proteins were made using conventional cloning and expression procedures. Secondary and tertiary structural features of the proteins were analyzed using spectral methods. Structural stabilities of the proteins were analyzed using chemical and thermal denaturation methods. Self-aggregation was monitored using extrinsic spectral probes. Molecular modeling was used to compare the structural features of the two proteins. Results: While the wild type and mutant have the same secondary structure, molecular modeling and fluorescence analysis suggest the mutant to have a more open tertiary structure, with a larger hydrophobic surface. Experiments using extrinsic probes reveal that the mutant readily self-aggregates, with the suggestion that the aggregates might be similar to amyloidogenic fibrils. Chemical denaturation indicates that while the wild type exhibits the classic two-state transition, V42M goes through an intermediate state, and has a distinctly lower stability than the wild type. The temperature of thermal unfolding of the mutant is also distinctly lower. Further, the mutant readily precipitates and scatters light more easily than the wild type. Conclusion: The replacement of valine in position 42 by the longer and bulkier methionine in human γS-crystallin perturbs the compact β-sheet core packing topology in the N-terminal domain of the molecule, exposes nonpolar residues thereby increasing the surface hydrophobicity and weakens the stability of the protein, thus promoting self-aggregation leading to light scattering particles. This set of changes in the properties of the mutant offers a molecular insight into the mechanism of opacification.
ACCESSION #
84709801

 

Related Articles

  • Effect of SkQ1 eye drops on the rat lens metabolomic composition and the chaperone activity of α-crystallin. Yanshole, L.; Yanshole, V.; Snytnikova, O.; Fursova, A.; Kolosova, N.; Tsentalovich, Yu.; Sagdeev, R. // Doklady Biochemistry & Biophysics;Sep2015, Vol. 464 Issue 1, p341 

    The ability of SkQ1 eye drops to slow down the cataract development is demonstrated on the senescence-accelerated OXYS rats: the SkQ1 treatment leads to the considerable improvement of the lens condition as compared to the control group. The comparison of the chaperone activities of...

  • The Congenital Cataract-Linked G61C Mutation Destabilizes γD-Crystallin and Promotes Non-Native Aggregation. Wang Zhang; Hong-Chen Cai; Fei-Feng Li; Yi-Bo Xi; Xu Ma; Yong-Bin Yan // PLoS ONE;2011, Vol. 6 Issue 5, p1 

    γD-crystallin is one of the major structural proteins in human eye lens. The solubility and stability of γD-crystallin play a crucial role in maintaining the optical properties of the lens during the life span of an individual. Previous study has shown that the inherited mutation G61C...

  • Comparative Analysis of Human γD-Crystallin Aggregation under Physiological and Low pH Conditions. Wu, Josephine W.; Chen, Mei-Er; Wen, Wen-Sing; Chen, Wei-An; Li, Chien-Ting; Chang, Chih-Kai; Lo, Chun-Hsien; Liu, Hwai-Shen; Wang, Steven S.-S. // PLoS ONE;Nov2014, Vol. 9 Issue 11, p1 

    Cataract, a major cause of visual impairment worldwide, is the opacification of the eye’s crystalline lens due to aggregation of the crystallin proteins. The research reported here is aimed at investigating the aggregating behavior of γ-crystallin proteins in various incubation...

  • Eye Drops: The Future of Cataract Treatment?  // Review of Optometry;8/15/2015, Vol. 152 Issue 8, p8 

    The article focuses on a study discussing the use of molecule lanosterol for the treatment of cataract, conducted by researcher Ling Zhou and colleagues. Topics include surgical treatment of cataract in the U.S.; production of lanosterol naturally by human body; and role of lanosterol in...

  • New Surgical Technique.  // USA Today Magazine;Feb90, Vol. 118 Issue 2537, p3 

    Reports on the development of a new cataract removal procedure based on magnetic principles by researchers at Aura Medical Systems Inc. Description of how the operation works; Injection of a tiny magnetic bead by syringe into the cataract.

  • Central corneal thickness in children with congenital cataract and children with surgical aphakia: a case-control study. A P C Lupinacci // British Journal of Ophthalmology;Mar2009, Vol. 93 Issue 3, p337 

    AIM: To measure the central corneal thickness (CCT) of children with congenital cataract and surgical aphakia. METHODS: Children with congenital cataract or surgical aphakia were prospectively recruited and divided into four groups: unilateral cataract (group 1, n = 14), bilateral cataract...

  • Single-Molecule Approach to Dispersed Kinetics and Dynamic Disorder: Probing Protein Conformational Fluctuation. Xie, X. Sunney // AIP Conference Proceedings;2003, Vol. 665 Issue 1, p323 

    I give a perspective of the single-molecule approach to protein conformational dynamics. The single-molecule, approach is extremely useful in studying dispersed kinetics and dynamic disorder. In particular, fluorescence lifetime experiments of natural fluorophores quenched by electron transfer...

  • Negotiating the speed bumps to fluorescence. Remington, S. James // Nature Biotechnology;Jan2002, Vol. 20 Issue 1, p28 

    Reports on two studies that describe fluorescent proteins (FP) with order-of-magnitude speed improvements to existing FP derivatives. Obstacles to the use of the molecules; Popularity of green FP as protein labels; Linkage of folding with other unrelated molecular properties.

  • AT A GLANCE.  // Scientist;Jan2015, Vol. 29 Issue 1, p31 

    The article presents information which compares fluorescent fusion proteins and the SunTag approach based on single-molecule imaging and multiple colors.

Share

Read the Article

Courtesy of THE LIBRARY OF VIRGINIA

Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics