ArticlePloS one2012
The mutation V42M distorts the compact packing of the human gamma-S-crystallin molecule, resulting in congenital cataract.
Article in PloS one, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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14 citing papers in PubMed, 25 citations in OpenAlex.
- Human Crystallin Variation and Cataract.Investigative ophthalmology & visual science · 2026Review
- The importance of the fourth Greek key motif of human γD-crystallin in maintaining lens transparency-the tale told by the tail.Molecular vision · 2024Article
- Human γS-Crystallin Mutation F10_Y11delinsLN in the First Greek Key Pair Destabilizes and Impairs Tight Packing Causing Cortical Lamellar Cataract.International journal of molecular sciences · 2023Article
- The Y46D Mutation Destabilizes Dense Packing of the Second Greek Key Pair of Human γC-Crystallin Causing Congenital Nuclear Cataracts.Biochemistry · 2023Article
- Impact of hydrogen peroxide on structure, stability, and aggregational properties of human γS-crystallin.Journal of biosciences · 2023Article
- Human γS-Crystallin-Copper Binding Helps Buffer against Aggregation Caused by Oxidative Damage.Biochemistry · 2020Article
- Human αB-crystallin discriminates between aggregation-prone and function-preserving variants of a client protein.Biochimica et biophysica acta. General subjects · 2020Article
- Multiple Aggregation Pathways in Human γS-Crystallin and Its Aggregation-Prone G18V Variant.Investigative ophthalmology & visual science · 2017Article
- Mutations and mechanisms in congenital and age-related cataracts.Experimental eye research · 2017Review
- Structural study of the G57W mutant of human gamma-S-crystallin, associated with congenital cataract.Molecular vision · 2016Article
- The cataract-associated V41M mutant of human γS-crystallin shows specific structural changes that directly enhance local surface hydrophobicity.Biochemical and biophysical research communications · 2014Article
- Preferential and specific binding of human αB-crystallin to a cataract-related variant of γS-crystallin.Structure (London, England : 1993) · 2013Article
- Structural analysis of the mutant protein D26G of human γS-crystallin, associated with Coppock cataract.Molecular vision · 2013Article
- Structural integrity of the Greek key motif in βγ-crystallins is vital for central eye lens transparency.PloS one · 2013Article
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Authors and funding
3 authors at 1 institution in 1 country.
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No grant is acknowledged in the PubMed record.
Abstract
backgroundHuman 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.
methodsBoth 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.
resultsWhile 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.
conclusionThe 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.
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