The unconventional regulation of non-muscle myosins

Abstract Myosins are actin-based molecular motors that power diverse forms of cellular motility across life. Initially characterized as the contractile machinery of muscle, the superfamily now includes numerous non-muscle classes with distinct cellular functions. Over the past decades, work across numerous actin-based systems has uncovered multiple modes of non-muscle myosin control. Recent advances now expand and, in some cases, challenge conventional regulatory paradigms, underscoring the complexity and adaptability of myosin function in cellular contexts. In this short review, I begin with a concise summary of the major canonical regulatory systems for non-muscle myosins. I follow this by highlighting the major novel regulatory findings from the last decade specifically relating to protein-binding partner activation, structural lipid-binding motifs, co-assembly of mixed classes of myosins, and the regulation of multi-motor complexes by the nanoscale organization of cellular actin. This review will appeal to the general scientific reader aiming to understand the mechanisms regulating myosins outside of the context of muscle and the current state of the non-muscle myosin field.