TY - JOUR

T1 - Extracellular matrix sensing via modulation of orientational order of integrins and F-actin in focal adhesions

AU - Grudtsyna, Valeriia

AU - Packirisamy, Swathi

AU - Bidone, Tamara C.

AU - Swaminathan, Vinay

N1 - Publisher Copyright: © 2023 Grudtsyna et al.

PY - 2023/8/10

Y1 - 2023/8/10

N2 - Specificity of cellular responses to distinct cues from the ECM requires precise and sensitive decoding of physical information. However, how known mechanisms of mechanosensing like force-dependent catch bonds and conformational changes in FA proteins can confer that this sensitivity is not known. Using polarization microscopy and computational modeling, we identify dynamic changes in an orientational order of FA proteins as a molecular organizational mechanism that can fine-tune cell sensitivity to the ECM. We find that αV integrins and F-actin show precise changes in the orientational order in an ECM-mediated integrin activation-dependent manner. These changes are sensitive to ECM density and are regulated independent of myosin-II activity though contractility can enhance this sensitivity. A molecular-clutch model demonstrates that the orientational order of integrin-ECM binding coupled to directional catch bonds can capture cellular responses to changes in ECM density. This mechanism also captures decoupling of ECM density sensing from stiffness sensing thus elucidating specificity. Taken together, our results suggest relative geometric organization of FA molecules as an important molecular architectural feature and regulator of mechanotransduction.

AB - Specificity of cellular responses to distinct cues from the ECM requires precise and sensitive decoding of physical information. However, how known mechanisms of mechanosensing like force-dependent catch bonds and conformational changes in FA proteins can confer that this sensitivity is not known. Using polarization microscopy and computational modeling, we identify dynamic changes in an orientational order of FA proteins as a molecular organizational mechanism that can fine-tune cell sensitivity to the ECM. We find that αV integrins and F-actin show precise changes in the orientational order in an ECM-mediated integrin activation-dependent manner. These changes are sensitive to ECM density and are regulated independent of myosin-II activity though contractility can enhance this sensitivity. A molecular-clutch model demonstrates that the orientational order of integrin-ECM binding coupled to directional catch bonds can capture cellular responses to changes in ECM density. This mechanism also captures decoupling of ECM density sensing from stiffness sensing thus elucidating specificity. Taken together, our results suggest relative geometric organization of FA molecules as an important molecular architectural feature and regulator of mechanotransduction.

U2 - 10.26508/lsa.202301898

DO - 10.26508/lsa.202301898

M3 - Journal article

C2 - 37463754

AN - SCOPUS:85165520943

VL - 6

JO - Life Science Alliance

JF - Life Science Alliance

SN - 2575-1077

IS - 10

M1 - e202301898

ER -