α-catenin is a key mechanosensor that forms force-dependent interactions with F-actin, thereby coupling the cadherin-catenin complex to the actin cytoskeleton at adherens junctions (AJs). However, the molecular mechanisms by which α-catenin engages F-actin under tension remained elusive. Here we show that the α1-helix of the α-catenin actin-binding domain (αcat-ABD) is a mechanosensing motif that regulates tension-dependent F-actin binding and bundling. αcat-ABD containing an α1-helix-unfolding mutation (H1) shows enhanced binding to F-actin in vitro. Although full-length α-catenin-H1 can generate epithelial monolayers that resist mechanical disruption, it fails to support normal AJ regulation in vivo. Structural and simulation analyses suggest that α1-helix allosterically controls the actin-binding residue V796 dynamics. Crystal structures of αcat-ABD-H1 homodimer suggest that α-catenin can facilitate actin bundling while it remains bound to E-cadherin. We propose that force-dependent allosteric regulation of αcat-ABD promotes dynamic interactions with F-actin involved in actin bundling, cadherin clustering, and AJ remodeling during tissue morphogenesis.
Myosin heavy chain 7b (MYH7b) is an evolutionarily ancient member of the sarcomeric myosin family, which typically supports striated muscle function. However, in mammals, alternative splicing prevents MYH7b protein production in cardiac and most skeletal muscles and limits expression to a subset of specialized muscles and certain nonmuscle environments. In contrast, MYH7b protein is abundant in python cardiac and skeletal muscles. Although the MYH7b expression pattern diverges in mammals versus reptiles, MYH7b shares high sequence identity across species. So, it remains unclear how mammalian MYH7b function may differ from that of other sarcomeric myosins and whether human and python MYH7b motor functions diverge as their expression patterns suggest. Thus, we generated recombinant human and python MYH7b protein and measured their motor properties to investigate any species-specific differences in activity. Our results reveal that despite having similar working strokes, the MYH7b isoforms have slower actin-activated ATPase cycles and actin sliding velocities than human cardiac β-MyHC. Furthermore, python MYH7b is tuned to have slower motor activity than human MYH7b because of slower kinetics of the chemomechanical cycle. We found that the MYH7b isoforms adopt a higher proportion of myosin heads in the ultraslow, super-relaxed state compared with human cardiac β-MyHC. These findings are supported by molecular dynamics simulations that predict MYH7b preferentially occupies myosin active site conformations similar to those observed in the structurally inactive state. Together, these results suggest that MYH7b is specialized for slow and energy-conserving motor activity and that differential tuning of MYH7b orthologs contributes to species-specific biological roles.
Medical schools and other higher education institutions across the United States are grappling with how to respond to racism on and off campus. Institutions and their faculty, administrators, and staff have examined their policies and practices, missions, curricula, and the representation of racial and ethnic minority groups among faculty, staff, and students. In addition, student-led groups, such as White Coats for Black Lives, have emerged to critically evaluate medical school curricula and advocate for change. Another approach to addressing racism has been a focus on the role of professionalism, which has been variably defined as values, traits, behaviors, morality, humanism, a role, an identity, and even a social contract.In this article, the authors consider the potential role that professionalism might play in responding to racism in medical education and at medical schools. They identify 3 concerns central to this idea. The first concern is differing definitions of what the problem being addressed really is. Is it isolated racist acts or institutional racism that is a reflection of white supremacy? The second concern is the notion that professionalism may be used as a tool of social control to maintain the interests of the social groups that dominate medicine. The third concern is that an overly simplistic application of professionalism, regardless of how the problem of racism is defined, may result in trainees practicing professionalism that is performative rather than internally motivated. The authors conclude that professionalism may complement a more systematic and holistic approach to addressing racism and white supremacy in medical education, but it is an insufficient stand-alone tool to address this core problem.
