An ensemble of flexible conformations underlies mechanotransduction by the cadherin–catenin adhesion complex

Martin Bush; Bashir M. Alhanshali; Shuo Qian; Christopher B. Stanley; William T. Heller; Tsutomu Matsui; Thomas M. Weiss; Iain D. Nicholl; Thomas Walz; David J.E. Callaway; Zimei Bu

doi:10.1073/pnas.1911489116

An ensemble of flexible conformations underlies mechanotransduction by the cadherin–catenin adhesion complex

Martin Bush, Bashir M. Alhanshali, Shuo Qian, Christopher B. Stanley, William T. Heller, Tsutomu Matsui, Thomas M. Weiss, Iain D. Nicholl, Thomas Walz, David J.E. Callaway, Zimei Bu

Research output: Contribution to journal › Article › peer-review

32 Scopus citations

Abstract

The cadherin–catenin adhesion complex is the central component of the cell–cell adhesion adherens junctions that transmit mechanical stress from cell to cell. We have determined the nanoscale structure of the adherens junction complex formed by the α-catenin•β-catenin•epithelial cadherin cytoplasmic domain (ABE) using negative stain electron microscopy, small-angle X-ray scattering, and selective deuteration/small-angle neutron scattering. The ABE complex is highly pliable and displays a wide spectrum of flexible structures that are facilitated by protein-domain motions in α- and β-catenin. Moreover, the 107-residue intrinsically disordered N-terminal segment of β-catenin forms a flexible “tongue” that is inserted into α-catenin and participates in the assembly of the ABE complex. The unanticipated ensemble of flexible conformations of the ABE complex suggests a dynamic mechanism for sensitivity and reversibility when transducing mechanical signals, in addition to the catch/slip bond behavior displayed by the ABE complex under mechanical tension. Our results provide mechanistic insight into the structural dynamics for the cadherin–catenin adhesion complex in mechanotransduction.

Original language	English
Pages (from-to)	21545-21555
Number of pages	11
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	116
Issue number	43
DOIs	https://doi.org/10.1073/pnas.1911489116
State	Published - Oct 22 2019

Funding

ACKNOWLEDGMENTS. This research was funded by NSF Grant MCB-1817684 (to Z.B.) and National Center for Research Resources Grant 2G12 RR003060 (to City College of New York). A portion of the research conducted at Oak Ridge National Laboratory’s Spallation Neutron Source and High Flux Isotope Reactor was sponsored by the Scientific User Facilities Division, Office of Basic Energy Sciences, US Department of Energy (DOE). The Bio-SANS of the Center for Structural Molecular Biology at the High Flux Isotope Reactor is supported by the Office of Biological and Environmental Research of the DOE. Use of the SSRL, Stanford Linear Accelerator Center’s is supported by DOE, Office of Science, Office of Basic Energy Sciences Contract DE-AC02-76SF00515. The SSRL Structural Molecular Biology Program is supported by the DOE Office of Biological and Environmental Research and NIH, National Institute of General Medical Sciences (NIGMS) Grant P41 GM103393. We thank Carrie Gao for technical support during the SANS experiments at Spallation Neutron Source. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the NIGMS or the NIH. This research was funded by NSF Grant MCB-1817684 (to Z.B.) and National Center for Research Resources Grant 2G12 RR003060 (to City College of New York). A portion of the research conducted at Oak Ridge National Laboratory?s Spallation Neutron Source and High Flux Isotope Reactor was sponsored by the Scientific User Facilities Division, Office of Basic Energy Sciences, US Department of Energy (DOE). The Bio-SANS of the Center for Structural Molecular Biology at the High Flux Isotope Reactor is supported by the Office of Biological and Environmental Research of the DOE. Use of the SSRL, Stanford Linear Accelerator Center?s is supported by DOE, Office of Science, Office of Basic Energy Sciences Contract DE-AC02-76SF00515. The SSRL Structural Molecular Biology Program is supported by the DOE Office of Biological and Environmental Research and NIH, National Institute of General Medical Sciences (NIGMS) Grant P41 GM103393. We thank Carrie Gao for technical support during the SANS experiments at Spallation Neutron Source. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the NIGMS or the NIH.

Funders	Funder number
Center for Structural Molecular Biology
DOE Office of Biological and Environmental Research
Office of Basic Energy Sciences
Office of Biological and Environmental Research
SSRL
Scientific User Facilities Division
Stanford Linear Accelerator Center
US Department of Energy
National Science Foundation	MCB-1817684
National Institutes of Health
U.S. Department of Energy
National Institute of General Medical Sciences	P41GM103393
National Center for Research Resources	2G12 RR003060
National Sleep Foundation
Office of Science	DE-AC02-76SF00515
Basic Energy Sciences
Biological and Environmental Research
Oak Ridge National Laboratory
City College of New York

Keywords

Adherens junction
Mechanotransduction
Negative stain electron microscopy
Small-angle X-ray scattering
Small-angle neutron scattering

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10.1073/pnas.1911489116

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Bush, M., Alhanshali, B. M., Qian, S., Stanley, C. B., Heller, W. T., Matsui, T., Weiss, T. M., Nicholl, I. D., Walz, T., Callaway, D. J. E., & Bu, Z. (2019). An ensemble of flexible conformations underlies mechanotransduction by the cadherin–catenin adhesion complex. Proceedings of the National Academy of Sciences of the United States of America, 116(43), 21545-21555. https://doi.org/10.1073/pnas.1911489116

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abstract = "The cadherin–catenin adhesion complex is the central component of the cell–cell adhesion adherens junctions that transmit mechanical stress from cell to cell. We have determined the nanoscale structure of the adherens junction complex formed by the α-catenin•β-catenin•epithelial cadherin cytoplasmic domain (ABE) using negative stain electron microscopy, small-angle X-ray scattering, and selective deuteration/small-angle neutron scattering. The ABE complex is highly pliable and displays a wide spectrum of flexible structures that are facilitated by protein-domain motions in α- and β-catenin. Moreover, the 107-residue intrinsically disordered N-terminal segment of β-catenin forms a flexible “tongue” that is inserted into α-catenin and participates in the assembly of the ABE complex. The unanticipated ensemble of flexible conformations of the ABE complex suggests a dynamic mechanism for sensitivity and reversibility when transducing mechanical signals, in addition to the catch/slip bond behavior displayed by the ABE complex under mechanical tension. Our results provide mechanistic insight into the structural dynamics for the cadherin–catenin adhesion complex in mechanotransduction.",

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Bush, M, Alhanshali, BM, Qian, S , Stanley, CB , Heller, WT, Matsui, T, Weiss, TM, Nicholl, ID, Walz, T, Callaway, DJE & Bu, Z 2019, 'An ensemble of flexible conformations underlies mechanotransduction by the cadherin–catenin adhesion complex', Proceedings of the National Academy of Sciences of the United States of America, vol. 116, no. 43, pp. 21545-21555. https://doi.org/10.1073/pnas.1911489116

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AU - Matsui, Tsutomu

AU - Weiss, Thomas M.

AU - Nicholl, Iain D.

AU - Walz, Thomas

AU - Callaway, David J.E.

AU - Bu, Zimei

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AB - The cadherin–catenin adhesion complex is the central component of the cell–cell adhesion adherens junctions that transmit mechanical stress from cell to cell. We have determined the nanoscale structure of the adherens junction complex formed by the α-catenin•β-catenin•epithelial cadherin cytoplasmic domain (ABE) using negative stain electron microscopy, small-angle X-ray scattering, and selective deuteration/small-angle neutron scattering. The ABE complex is highly pliable and displays a wide spectrum of flexible structures that are facilitated by protein-domain motions in α- and β-catenin. Moreover, the 107-residue intrinsically disordered N-terminal segment of β-catenin forms a flexible “tongue” that is inserted into α-catenin and participates in the assembly of the ABE complex. The unanticipated ensemble of flexible conformations of the ABE complex suggests a dynamic mechanism for sensitivity and reversibility when transducing mechanical signals, in addition to the catch/slip bond behavior displayed by the ABE complex under mechanical tension. Our results provide mechanistic insight into the structural dynamics for the cadherin–catenin adhesion complex in mechanotransduction.

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KW - Small-angle X-ray scattering

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An ensemble of flexible conformations underlies mechanotransduction by the cadherin–catenin adhesion complex

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