Exploring force-driven stochastic folding dynamics in mechano-responsive proteins and implications in phenotypic variation
Abstract Single-point mutations are pivotal in molecular zoology, shaping functions and influencing genetic diversity and evolution. Here we study three such genetic variants of a mechano-responsive protein, cadherin-23, that uphold the structural integrity of the protein, but showcase distinct geno...
Saved in:
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-01-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-55946-3 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832585549889667072 |
|---|---|
| author | Pritam Saha Vishavdeep Vashisht Ojas Singh Amin Sagar Gaurav Kumar Bhati Surbhi Garg Sabyasachi Rakshit |
| author_facet | Pritam Saha Vishavdeep Vashisht Ojas Singh Amin Sagar Gaurav Kumar Bhati Surbhi Garg Sabyasachi Rakshit |
| author_sort | Pritam Saha |
| collection | DOAJ |
| description | Abstract Single-point mutations are pivotal in molecular zoology, shaping functions and influencing genetic diversity and evolution. Here we study three such genetic variants of a mechano-responsive protein, cadherin-23, that uphold the structural integrity of the protein, but showcase distinct genotypes and phenotypes. The variants exhibit subtle differences in transient intra-domain interactions, which in turn affect the anti-correlated motions among the constituent β-strands. In nature, the variants experience declining functions with aging at different rates. We expose these variants to constant and oscillatory forces using magnetic tweezer, and measure variations in stochastic folding dynamics. All variants exhibit multiple microstates under force. However, the protein variant with higher number of intra-domain interactions exhibits transitions among the heterogeneous microstates for larger extent of forces and persisted longer. Conversely, the protein variant with weaker inter-strand correlations exhibits greater unfolding cooperativity and faster intrinsic folding, although its folding-energy landscape is more susceptible to distortion under tension. Our study thus deciphers the molecular mechanisms underlying the variations in force-adaptations and proposes a mechanical relation between genotype and phenotype. |
| format | Article |
| id | doaj-art-192ee2149fd54d0b95209b3704d74e11 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-192ee2149fd54d0b95209b3704d74e112025-01-26T12:40:22ZengNature PortfolioNature Communications2041-17232025-01-0116111410.1038/s41467-025-55946-3Exploring force-driven stochastic folding dynamics in mechano-responsive proteins and implications in phenotypic variationPritam Saha0Vishavdeep Vashisht1Ojas Singh2Amin Sagar3Gaurav Kumar Bhati4Surbhi Garg5Sabyasachi Rakshit6Department of Chemical Sciences, Indian Institute of Science Education and Research MohaliDepartment of Chemical Sciences, Indian Institute of Science Education and Research MohaliDepartment of Chemical Sciences, Indian Institute of Science Education and Research MohaliBicycleTx LimitedDepartment of Chemical Sciences, Indian Institute of Science Education and Research MohaliDepartment of Chemical Sciences, Indian Institute of Science Education and Research MohaliDepartment of Chemical Sciences, Indian Institute of Science Education and Research MohaliAbstract Single-point mutations are pivotal in molecular zoology, shaping functions and influencing genetic diversity and evolution. Here we study three such genetic variants of a mechano-responsive protein, cadherin-23, that uphold the structural integrity of the protein, but showcase distinct genotypes and phenotypes. The variants exhibit subtle differences in transient intra-domain interactions, which in turn affect the anti-correlated motions among the constituent β-strands. In nature, the variants experience declining functions with aging at different rates. We expose these variants to constant and oscillatory forces using magnetic tweezer, and measure variations in stochastic folding dynamics. All variants exhibit multiple microstates under force. However, the protein variant with higher number of intra-domain interactions exhibits transitions among the heterogeneous microstates for larger extent of forces and persisted longer. Conversely, the protein variant with weaker inter-strand correlations exhibits greater unfolding cooperativity and faster intrinsic folding, although its folding-energy landscape is more susceptible to distortion under tension. Our study thus deciphers the molecular mechanisms underlying the variations in force-adaptations and proposes a mechanical relation between genotype and phenotype.https://doi.org/10.1038/s41467-025-55946-3 |
| spellingShingle | Pritam Saha Vishavdeep Vashisht Ojas Singh Amin Sagar Gaurav Kumar Bhati Surbhi Garg Sabyasachi Rakshit Exploring force-driven stochastic folding dynamics in mechano-responsive proteins and implications in phenotypic variation Nature Communications |
| title | Exploring force-driven stochastic folding dynamics in mechano-responsive proteins and implications in phenotypic variation |
| title_full | Exploring force-driven stochastic folding dynamics in mechano-responsive proteins and implications in phenotypic variation |
| title_fullStr | Exploring force-driven stochastic folding dynamics in mechano-responsive proteins and implications in phenotypic variation |
| title_full_unstemmed | Exploring force-driven stochastic folding dynamics in mechano-responsive proteins and implications in phenotypic variation |
| title_short | Exploring force-driven stochastic folding dynamics in mechano-responsive proteins and implications in phenotypic variation |
| title_sort | exploring force driven stochastic folding dynamics in mechano responsive proteins and implications in phenotypic variation |
| url | https://doi.org/10.1038/s41467-025-55946-3 |
| work_keys_str_mv | AT pritamsaha exploringforcedrivenstochasticfoldingdynamicsinmechanoresponsiveproteinsandimplicationsinphenotypicvariation AT vishavdeepvashisht exploringforcedrivenstochasticfoldingdynamicsinmechanoresponsiveproteinsandimplicationsinphenotypicvariation AT ojassingh exploringforcedrivenstochasticfoldingdynamicsinmechanoresponsiveproteinsandimplicationsinphenotypicvariation AT aminsagar exploringforcedrivenstochasticfoldingdynamicsinmechanoresponsiveproteinsandimplicationsinphenotypicvariation AT gauravkumarbhati exploringforcedrivenstochasticfoldingdynamicsinmechanoresponsiveproteinsandimplicationsinphenotypicvariation AT surbhigarg exploringforcedrivenstochasticfoldingdynamicsinmechanoresponsiveproteinsandimplicationsinphenotypicvariation AT sabyasachirakshit exploringforcedrivenstochasticfoldingdynamicsinmechanoresponsiveproteinsandimplicationsinphenotypicvariation |