Biology subjects

SAHA, P.

Publications and source records attributed to SAHA, P..

3 recordsLinked to original sources

bioRxiv2026

CRTAC1-A reprograms extracellular matrix viscoelasticity to constrain glioma progression

Mechanical remodeling of the extracellular matrix (ECM) influences glioma progression, yet the molecular regulators that control tumor matrix mechanics remain poorly understood. By comparing low-grade gliomas (LGGs), associated with improved patient survival, with glioblastomas (GBMs), which carry a poor prognosis, we identified the cartilage-derived ECM protein CRTAC1-A as enriched in LGGs and significantly reduced in GBMs, with elevated expression correlating with improved patient survival. Restoration of CRTAC1-A suppressed glioma cell proliferation and invasion and enhanced temozolomide efficacy in three-dimensional tumor spheroid models. Mechanistically, CRTAC1-A directly interacts with collagen I and reorganizes collagen networks across multiple length scales, generating a mechanically compliant yet structurally resilient ECM with reduced stiffness, enhanced elastic recovery, and resistance to persistent remodeling. This viscoelastic normalization limits invasive remodeling while preserving matrix permeability and drug penetration. Together, these findings identify CRTAC1-A as a reversible regulator of tumor ECM mechanics that suppresses glioma malignancy.

cancer biology↗

bioRxiv2025

Cadherin-23 Mutations Cause Calcium-Dependent, Allele-Sensitive Mechanosensory Defects

Point mutations in tip-link proteins, molecular filaments that transmit mechanical tension from sound-stimuli to sensory transduction channels, are abundantly associated with hereditary hearing loss. Intriguingly, many of these mutations lie far from the protein binding interface and do not affect balance or vision. Here, we explore two such distal mutations that cause congenital deafness in homozygous individuals and progressive hearing loss in compound heterozygotes, while sparing vestibular and retinal function. Using a combination of protein engineering, single-molecule force spectroscopy, and molecular dynamics simulations, we reconstructed wild-type and mutant tip-link complexes to examine how these mutations alter their mechanical structure. Our experiments reveal that the mutations subtly change the folding kinetics and force-dependent rupture behavior of the tip-link complexes, particularly under low calcium conditions that mimic the cochlear environment. These mechanical alterations were significantly attenuated at higher calcium concentrations, consistent with the calcium-rich milieu of the vestibular and retinal tissues. Together, our findings suggest that distal mutations can compromise tip-link function in a calcium-sensitive manner, offering a mechanistic explanation for how the same mutations selectively impair hearing while leaving balance and vision intact.

biophysics↗

bioRxiv2025

Titin as a mechanical damper: Balancing Stability and longevity through inter-domain linker design

Titin, a giant protein ([~]3-4 MDa), functions as a molecular-spring to regulate muscle elasticity. More than 90% of Titin is composed of domains that absorb mechanical energy and undergo stochastic unfolding-refolding under tension ([~]tens of pN). These domains are connected in tandem by interdomain linkers (IDLs), which constitute less than 10% of the total mass. Despite their small genomic footprint, bioinformatics mapping suggests that IDLs have an outsized impact on protein mechanics, potentially contributing to disease pathology. Using magnetic tweezers, here we examine how linkers influence mechano-response of domains to constant and oscillatory forces. We found that short linkers limit interdomain movement and promote first-order cooperative folding transitions of domains. In contrast, long flexible linkers induce creep-like deformations interspersed with sharp, stepwise transitions. Surprisingly, linkers that improve domain-stability resist unfolding under constant pulling forces, but lose power retention faster under oscillatory forces. Our findings reveal a trade-off between mechanical stability and energy retention in titin, a key muscle protein. These insights offer new design principles for mechano-responsive protein engineering. TeaserTiny linkers fine-tune how bulky domains in titin respond to force.

biophysics↗