Research

STRETCHING AND SORTING LIFE

Mechanotransduction – Cellular Adhesion – Structural Biology – Molecular Dynamics Simulations – Protein Biochemistry and Biophysics

Living organisms rely on macroscopic and microscopic structures that produce and transform force to survive: from cell volume regulation to sound transduction and cellular adhesion, handling of forces is essential to life.  Research in the Sotomayor group focuses on elucidating the molecular mechanisms underlying vertebrate mechanosensation and selective cellular adhesion. We use interdisciplinary and quantitative approaches to reveal structure-function relationships in macromolecular complexes such as those found in the mechanotransduction apparatus of inner-ear hair cells and in the cadherin adhesion machinery of epithelial tissues and synapses. These systems are ideal to study biological function at multiple levels: from single molecules to adhesion complexes and tissues, even up to animal behavior. Our combined experimental-computational research approach provides a unique structural framework to understand protein mechanics and function in hearing and balance, as well as in morphogenesis, cancer, and neuronal connectivity. It also provides the basis for engineering protein function in the context of mechanotransduction and cellular adhesion.

Ultimately, the success in understanding the mechanisms at play in mechanotransduction and adhesion will be measured by our ability to modify and manipulate these systems at will, for instance by creating stronger tip links, softer gating springs, transduction channels with reversed selectivity, cadherin bonds with designed specificity and mechanosensitivity, as well as photoswitchable adhesion molecules that can be used to turn on and off neuronal circuits or modify tissue development and mechanics.

CURRENT PROJECTS

Structural Biology and Simulations of Proteins Involved in Mechanosensation

Force Spectroscopy of Hair-Cell Tip Links

Molecular Connectomics: Binding Specificity in Novel Cadherin Complexes

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Structural Biology and Simulations of Proteins Involved in Mechanosensation

Mechanical forces produced by sound, gravity, and osmotic pressure are sensed by different organisms through multiple mechanisms that usually involve mechanosensitive ion channels and accessory proteins conveying tension. We are using a combination of X-ray crystallography and computational biology to determine the structure and dynamics of macromolecular complexes involved in vertebrate mechanotransduction. We are particularly interested in structures of cadherins and membrane proteins and ion channels involved in sound perception, as well as in testable predictions from large-scale all-atom molecular dynamics simulations of force transduction.

Selected Related Publications

R. Araya-Secchi, B. L. Neel, and M. Sotomayor. “An elastic element in the protocadherin-15 tip link of the inner ear” Nature Communications, 7:13458, 2016.

M. Sotomayor, W. A. Weihofen, R. Gaudet, and D. P. Corey. “Structure of a Force-Conveying Cadherin Bond Essential for Inner-Ear Mechanotransduction” Nature, 492:128-132, 2012.

M. Sotomayor*, V. Vasquez*, E. Perozo, and K. Schulten. “Ion Conduction through MscS as Determined by Electrophysiology and Simulation” Biophysical Journal, 92:886-902, 2007.

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Force Spectroscopy of Hair-Cell Tip Links

Hair cells are specialized and sensitive mechanoreceptors that transform mechanical stimuli into electrical signals in the inner ear. The tip link bond is essential for hair-cell mechanotransduction but little is known about the forces it can withstand and the molecular mechanisms underlying its noise-induced damage. The discovery of the tip-link molecular components and our resolution of the first X-ray crystallographic structure of part of the bond opened the door to explore the molecular determinants of its strength. In collaboration with the Corey/Wong labs, we are using single-molecule force spectroscopy experiments and simulations to probe the strength of the tip-link bond and discover molecular mechanisms associated with its formation, rupture and malfunction in deafness. The knowledge gained will allow us to design synthetic tip link bonds with enhanced mechanical strength, as well as molecular sensors to measure forces in vivo.

Movie – Forced Unbinding of Tip Link Cadherins

Selected Related Publications

M. A. Koussa, M. Sotomayor, W. Wong. “Protocol for sortase-mediated construction of DNA-protein hybrids and functional nanostructures” Methods, 67:134-141, 2014.

M. Sotomayor, W. A. Weihofen, R. Gaudet, and D. P. Corey. “Structure of a Force-Conveying Cadherin Bond Essential for Inner-Ear Mechanotransduction” Nature, 492:128-132, 2012.

M. Sotomayor*, W. A. Weihofen*, R. Gaudet, and D. P. Corey. “Structural Determinants of Cadherin-23 Function in Hearing and Deafness” Neuron, 66:85-100, 2010.

M. Sotomayor and K. Schulten. “Single-Molecule Experiments in Vitro and in SilicoScience, 316:1144-1148, 2007.

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Molecular Connectomics: Binding Specificity in Novel Cadherin Complexes

Selective cell-cell adhesion is essential for tissue development and formation of complex and structured multicellular organs. Multiple families of cell-adhesion molecules have been identified; the cadherin superfamily of calcium-dependent adhesion proteins is one of the largest and has been implicated in tissue and organ morphogenesis and cancer. We are using bioinformatics tools and high-throughput methodologies to discover novel cadherin complexes and reveal the structural determinants of their binding specificity and biological function. The knowledge gained from the biophysical and biochemical characterization of these complexes will allow us to design synthetic cadherins with specific affinities and mechanical strength, as well as photoswitchable adhesion interfaces to control tissue development and neuronal connectivity.

Selected Related Publications

S. R. Cooper, J. D. Jontes, and M. Sotomayor. “Structural determinants of adhesion by Protocadherin-19 and implications for its role in epilepsy” eLife, 5:e18529, 2016.

M. Sotomayor, R. Gaudet, D. P. Corey. “Sorting out a promiscuous superfamily: towards cadherin connectomics” Trends in Cell Biology, 24:524-536, 2014.

M. Sotomayor, W. A. Weihofen, R. Gaudet, and D. P. Corey. “Structure of a Force-Conveying Cadherin Bond Essential for Inner-Ear Mechanotransduction” Nature, 492:128-132, 2012.

M. Sotomayor and K. Schulten. “The Allosteric Role of the Ca++ Switch in Adhesion and Elasticity of C-Cadherin” Biophysical Journal, 94:4621-4633, 2008.

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