AI Insight
This study investigates how the heterotrimeric kinesin-2 motor complex (KIF3A/KIF3B/KAP3) regulates its own activity through a process called autoinhibition, in which the motor folds back on itself to suppress unwanted movement. Using cell-based knockout-rescue experiments and structural predictions, the researchers demonstrate that specific interactions between the motor domains and C-terminal coiled-coil and tail regions stabilize this folded, inactive state, and that a flexible segment within the coiled-coil stalk enables the required conformational changes. Critically, the same regions needed for autoinhibition are also required for stable motor assembly and for ciliogenesis, establishing a direct functional link between proper self-regulation and the ability to build and maintain cilia.
Why it matters
Kinesin-2 is essential for forming and maintaining cilia, hair-like cellular structures whose dysfunction underlies a class of human diseases known as ciliopathies, including conditions affecting kidney, vision, and respiratory function. Understanding the molecular logic of kinesin-2 autoinhibition may inform future strategies for targeting ciliary defects in these disorders.
⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
Autoinhibition is a fundamental regulatory mechanism for kinesins, including the heterotrimeric kinesin-2 complex (KIF3A/KIF3B/KAP3), which mediates cytoplasmic cargo transport and anterograde intraflagellar transport. In mammals, kinesin-2 is essential for ciliogenesis and ciliary function. Although a structural model of autoinhibited kinesin-2 has been proposed, further validation and functional analysis are needed. Here, we elucidate the mechanism and functional importance of kinesin-2 autoinhibition using cell-based assays guided by structural predictions. Through knockout-rescue experiments with chimeric KIF3A-KIF3B subunits, we show that subunit-specific interactions between the motor domains and the C-terminal coiled-coil domains and adjacent tail {beta}-hairpin motifs stabilize the autoinhibited state. Interestingly, these same C-terminal regions required for autoinhibition are required for stable heterodimerization of the motor. We further find that a flexible region within the coiled-coil stalk is required for this autoregulation and may facilitate the underlying conformation transitions. Furthermore, the capacity to autoinhibit directly correlates with the ability of mutant motors to support ciliogenesis, underscoring the significance of autoinhibition for motor function. Collectively, these findings define key subunit-specific interactions underlying kinesin-2 autoinhibition, identify elements that govern conformational transitions, and demonstrate that autoinhibition is essential for kinesin-2 function in ciliogenesis.