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Long-tailed class I myosins rely on tail-mediated phosphoinositide recognition for specific membrane recruitment #MMPMID41340053
Rajendraprasad G; Kyriazi D; Franz P; Bader A; Erent M; Uta P; Preller M; Scholz T; Tsiavaliaris G
Cell Commun Signal 2025[Dec]; 23 (1): 519 PMID41340053show ga
BACKGROUND: Class I myosins are essential mediators of membrane-cytoskeleton interactions that support key cellular processes such as endocytosis, secretion, intracellular trafficking, and mitosis. However, the mechanisms driving isoform-specific targeting to membrane domains enriched in signaling lipids as well as their stage-dependent recruitment to mitotic structures during cell division remain poorly defined. METHODS AND APPROACH: Using Dictyostelium discoideum as a highly phagocytic cell model, we demonstrate that long-tailed myosin-1 isoforms (myosin-1B, -1C, and - 1D) exhibit distinct lipid and cytoskeletal binding profiles shaped by their modular tails and variations within the phosphoinositide binding motif. Homology-based structural modelling of the PH-like lipid binding domain within the TH1 sequence, combined with molecular docking explains their differential lipid affinities. Kinetic equilibrium modelling with quantitative data suggests these differences enable cooperative or competitive isoform localization within cells providing a mechanism for temporally controlled recruitment of the myosins in response to dynamic changes in membrane composition and expression profiles. These biochemical insights are corroborated by confocal live-cell imaging, which reveals phosphoinositides-dependent localization dynamics and isoform-specific targeting of the myosins during vegetative growth and mitotic progression. RESULTS: Myosin-C exhibits phosphoinositide binding preferences nearly reciprocal to those of myosin-1D, especially between mono- and triple phosphorylated phosphoinositides, and shows the strongest tail-mediated, ATP-independent actin binding. Myosin-1B, in contrast, displays low affinity for monophosphorylated phosphoinositides, intermediate actin binding ability, and no microtubule interaction. The comparable affinities of all three myosins for PI(3,5)P(2) and PI(4,5)P(2), the major PIP species at the cell cortex, facilitate their accumulation at membrane protrusions. Live-cell imaging confirms that myosin-1D preferentially associates with PI(3,4,5)P(3)- and PI(3)P-enriched endosomes during macropinocytosis and phagocytosis, consistent with its higher binding affinity for these phosphoinositides. Conversely, myosin-1C localization is governed by both actin and phosphoinositides, enabling a rapid dissociation from early endosomes to retarget the cortex and accumulate at actin-rich phagocytic cup tips. Upon mitotic entry, myosin-1D, similar to myosin-1C, redistributes from endosomal compartments to the mitotic apparatus, where it decorates membrane-enclosed nuclear chromatin masses through its TH1 domain and later associates with spindle pole microtubules. This contrasts with myosin-1C, which selectively targets spindle microtubules throughout mitosis, reflecting its stronger microtubule-binding affinity. Inhibition of PI3-kinase disrupts membrane recruitment of both isoforms, confirming their phosphoinositide-dependent localization. These findings reveal an isoform-specific mechanism underlying myosin-1 targeting during endocytosis and mitosis. CONCLUSION: Collectively, these findings establish a phosphoinositide- and cytoskeleton-guided mechanism that governs myosin-1 isoform-specific functions, providing new insights into how motor proteins interpret complex lipid and cytoskeletal cues to regulate membrane remodelling and cytoskeletal dynamics across cellular states.
Cell+Commun+Signal 2025 ; 23 (1): 519
