Highly conserved talin isoforms encode distinct mechanical responses and ligand-binding capabilities
- 1Mechanobiology Institute, Department of Physics, National University of Singapore
Abstract
Talin is a central mechanosensitive adaptor that links integrins to the actin cytoskeleton and converts mechanical force into biochemical signals. Vertebrates express two highly homologous talin isoforms, talin-1 and talin-2, yet the molecular basis for their nonredundant functions remains poorly understood. Here, we investigate how isoform-specific sequence differences alter the mechanical response and ligand-binding capabilities of the talin rod. Using single-molecule force spectroscopy and biochemical binding assays, we show that talin-2 preserves the overall mechanical architecture of talin-1 but exhibits distinct mechanical responses in key rod regions. Talin-2 R7-R9 exhibits a previously unobserved three-domain cooperative unfolding pathway, while an alternative sequential pathway reveals early unfolding of R9 at substantially lower force than in talin-1. Strikingly, talin-2 R4-R6 has acquired two additional mechanically regulated interactions: a previously unrecognized vinculin-binding site in R5 and an A-kinase anchoring protein (AKAP) region within R5-R6 that recruits protein kinase A (PKA). Together with the conserved R9 AKAP site, this establishes two spatially separated, mechanically regulated PKA-anchoring regions within the talin-2 scaffold. These findings establish that isoform-specific sequence divergence not only reshapes the mechanical response of the talin scaffold but also expands its repertoire of force-regulated interactions, providing a mechanism for the assembly of different structural and signaling complexes in an isoform-dependent manner.
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BibTeX
@misc{guo2026highly,
title = {{Highly conserved talin isoforms encode distinct mechanical responses and ligand-binding capabilities}},
author = {Y. Guo and D. Guttula and M. Yao and D. M. Cooper and N. Ball and B. Klapholz and A. Price and A. Howe and B. T. Goult and J. Yan},
howpublished = {bioRxiv},
year = {2026},
month = nov,
doi = {10.64898/2026.11.05.764451},
url = {https://www.biorxiv.org/content/10.64898/2026.11.05.764451v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Highly conserved talin isoforms encode distinct mechanical responses and ligand-binding capabilities
AU - Y. Guo
AU - D. Guttula
AU - M. Yao
AU - D. M. Cooper
AU - N. Ball
AU - B. Klapholz
AU - A. Price
AU - A. Howe
AU - B. T. Goult
AU - J. Yan
PY - 2026
DA - 2026/11/05
PB - bioRxiv
DO - 10.64898/2026.11.05.764451
UR - https://www.biorxiv.org/content/10.64898/2026.11.05.764451v1
AB - Talin is a central mechanosensitive adaptor that links integrins to the actin cytoskeleton and converts mechanical force into biochemical signals. Vertebrates express two highly homologous talin isoforms, talin-1 and talin-2, yet the molecular basis for their nonredundant functions remains poorly understood. Here, we investigate how isoform-specific sequence differences alter the mechanical response and ligand-binding capabilities of the talin rod. Using single-molecule force spectroscopy and biochemical binding assays, we show that talin-2 preserves the overall mechanical architecture of talin-1 but exhibits distinct mechanical responses in key rod regions. Talin-2 R7-R9 exhibits a previously unobserved three-domain cooperative unfolding pathway, while an alternative sequential pathway reveals early unfolding of R9 at substantially lower force than in talin-1. Strikingly, talin-2 R4-R6 has acquired two additional mechanically regulated interactions: a previously unrecognized vinculin-binding site in R5 and an A-kinase anchoring protein (AKAP) region within R5-R6 that recruits protein kinase A (PKA). Together with the conserved R9 AKAP site, this establishes two spatially separated, mechanically regulated PKA-anchoring regions within the talin-2 scaffold. These findings establish that isoform-specific sequence divergence not only reshapes the mechanical response of the talin scaffold but also expands its repertoire of force-regulated interactions, providing a mechanism for the assembly of different structural and signaling complexes in an isoform-dependent manner.
ER -