The structure of cell-matrix adhesions: the new frontier

Abstract

Adhesions between the cell and the extracellular matrix (ECM) are mechanosensitive multi-protein assemblies that transmit force across the cell membrane and regulate biochemical signals in response to the chemical and mechanical environment. These combined functions in force transduction, signaling and mechanosensing contribute to cellular phenotypes that span development, homeostasis and disease. These adhesions form, mature and disassemble in response to actin organization and physical forces that originate from endogenous myosin activity or external forces by the extracellular matrix. Despite advances in our understanding of the protein composition, interactions and regulation, our understanding of matrix adhesion structure and organization, how forces affect this organization, and how these changes dictate specific signaling events is limited. Insights across multiple structural levels are acutely needed to elucidate adhesion structure and ultimately the molecular basis of signaling and mechanotransduction. Here we describe the challenges and recent advances and prospects for unraveling the structure of cell-matrix adhesions and their response to force.

Figure 1. Strategy for correlating and integrating structures over scales

Multi-resolution workflow: Cells are grown on EM amenable substrates with: (A) fluorescence used to localize the regions of interest (B-D, bar in D = 2μm). This correlation approach also allows correlating dynamic information obtained by live-cell imaging, and (B) the underlying structure. (E) Surface representation of a cryo-tomogram from a region in the lamellipodium (blue in D). (F). Surface representation of a cryo-tomogram from a region in the lamella (red in D). The actin-network morphology appears markedly different. Ribosomes, clathrin, actin filaments, microtubules and Arp2/3-mediated actin branches can be readily identified in the reconstructions. We use the structural information of these assemblies previously obtained from reconstituted systems to aid analysis of the extracted motifs (for example [59-61]). Data kindly provided by Karen L.Anderson, Violaine Delorme, Wendy Ochoa, Matthias Eibauer, Florian Beck, Stephan Nickell and Niels Volkmann.