Abstract
Proteins as force-sensors respond to mechanical cues and regulate signaling in physiology. Proteins commonly connect the source and response points of mechanical cues in two conformations, independent proteins in end-to-end geometry and protein complexes in handshake geometry. The force-responsive property of independent proteins in end-to-end geometry is studied extensively using single-molecule force spectroscopy (SMFS). The physiological significance of the complex conformations in force-sensing is often disregarded as mere surge protectors. However, with the potential of force-steering, protein complexes possess a distinct mechano-responsive property over individual force-sensors. To decipher, we choose a force-sensing protein, cadherin-23, from tip-link complex and perform SMFS using end-to-end geometry and handshake complex geometry. We measure higher force-resilience of cadherin-23 with preferential shorter extensions in handshake mode of pulling over the direct mode. The handshake geometry drives the force-response of cadherin-23 through different potential-energy landscapes than direct pulling. Analysis of the dynamic network structure of cadherin-23 under tension indicates narrow force-distributions among residues in cadherin-23 in direct pulling, resulting in low force-dissipation paths and low resilience to force. Overall, the distinct and superior mechanical responses of cadherin-23 in handshake geometry than single protein geometry highlight a probable evolutionary drive of protein-protein complexes as force-conveyors over independent ones.
Highlights
Proteins as force-sensors respond to mechanical cues and regulate signaling in physiology
Using an Atomic Force Microscopy (AFM)-based force-generator, here we decipher the differences in the force-responsive properties of a biological spring protein, Cdh[23], between direct pulling (HAP) and indirect pulling via a partner (PAP)
Force application on Cdh[23] using its interacting partner Pcdh[15] and traditional handle-assisted pulling from terminals yield variable elastomeric responses of Cdh[23] exhibiting stronger mechanical fold architecture in the preceding approach
Summary
Proteins as force-sensors respond to mechanical cues and regulate signaling in physiology. Proteins commonly connect the source and response points of mechanical cues in two conformations, independent proteins in end-to-end geometry and protein complexes in handshake geometry. The force-responsive property of independent proteins in end-to-end geometry is studied extensively using single-molecule force spectroscopy (SMFS). The distinct and superior mechanical responses of cadherin-23 in handshake geometry than single protein geometry highlight a probable evolutionary drive of protein-protein complexes as force-conveyors over independent ones. In single-molecule force spectroscopy (SMFS), the protein of interest (POI) is either attached with marker polyproteins or DNA and pulled from one end with a mechanical spring This can be described as ‘handle (or hook)-assisted pulling’ (HAP). The fundamental question, whether the HAP based force-spectroscopy is suitable to decipher the force-responsive nature of proteins in the second type of force-sensors, remains still elusive. With an overarching objective of elucidating the evolutionary thirst for developing two configurationally different force-sensors, here, we plan to experimentally decipher the difference in the force-responsive properties of HAP and PAP and highlight the underlying molecular mechanisms
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