Cantrell, P. S. | bioRxiv Science

bioRxiv2025

The Desmoglein 2 interactome in primary neonatal cardiomyocytes

Mechanical coupling and chemical communication between cardiomyocytes are facilitated through a specialized adhesive structure known as the intercalated disc (ICD). The ICD is essential for heart organization and contraction. Yet, the network of adhesion, adaptor, and signaling proteins that form the ICD remains poorly defined. Here, we combined proximity labeling and quantitative mass spectrometry to identify proteins associated with the desmosomal cadherin, Desmoglein 2 (DSG2), in cultured neonatal cardiomyocytes. We identified over 300 proteins in the DSG2 interactome; half of which are shared with the N-cadherin (CDH2) interactome in cardiomyocytes. Proteins unique to DSG2 include the gap junction protein connexin 43 and the plakin family of cytolinker proteins. Comparison of the cardiomyocyte DSG2 interactome with the interactomes of desmosomal proteins from epithelia revealed only a small number of shared proteins. In cardiomyocytes, plakoglobin (JUP) and plakophilin 2 (PKP2) were the most abundant shared proteins between the DSG2 and CDH2 interactomes. PKP2 is a dynamic protein whose membrane recruitment in cardiomyocytes is tension-dependent. Our analysis of the DSG2 interactome provides a critical new dimension to the proteomic atlas of the essential molecular complexes required for cardiomyocyte adhesion.

cell biology↗

bioRxiv2018

The N-cadherin interactome in primary cardiomyocytes as defined by quantitative proximity proteomics.

The junctional complexes that couple cardiomyocytes must transmit the mechanical forces of contraction while maintaining adhesive homeostasis. The adherens junction (AJ) connects the actomyosin networks of neighboring cardiomyocytes and is required for proper heart function. Yet little is known about the molecular composition of the cardiomyocyte AJ or how it is organized to function under mechanical load. Here we define the architecture, dynamics and proteome of the cardiomyocyte AJ. Mouse neonatal cardiomyocytes assemble stable AJs along intercellular contacts with organizational and structural hallmarks similar to mature contacts. We combine quantitative mass spectrometry with proximity labeling to identify the N-cadherin (CDH2) interactome. We define over 350 proteins in this interactome, nearly 200 of which are unique to CDH2 and not part of the E-cadherin (CDH1) interactome. CDH2-specific interactors are comprised primarily of adaptor and adhesion proteins that promote junction specialization. Finally, we find evidence of dynamic interplay between AJ and Z-disc proteins. Together, our results provide novel insight into the cardiomyocyte AJ and provide a proteomic atlas for defining the molecular complexes that regulate cardiomyocyte intercellular adhesion.\n\nSummary StatementProximity proteomics reveals a specific and specialized N-cadherin (CDH2) interactome along the cell-cell contacts of primary cardiomyocytes.

cell biology↗