Kinesin-1 conformational dynamics are controlled by a cargo-sensitive TPR switch.

Area of Science:

• Molecular Biology
• Cell Biology
• Structural Biology

Background:

• Kinesin-1 is a motor protein complex essential for intracellular transport.
• It exists in a compact, autoinhibited state, activated by cargo-adaptor proteins.
• Short linear motifs (SLiMs) on adaptors interact with Kinesin Light Chain (KLC) tetratricopeptide repeat (TPR) domains.

Purpose of the Study:

• To elucidate the mechanism coupling SLiM recognition to activation-induced conformational changes in Kinesin-1.
• To investigate the structural consequences of SLiM binding to KLC-TPR domains within the holoenzyme.

Main Methods:

• Protein design
• Computational modeling
• Biophysical analysis
• Electron microscopy

Main Results:

• Coiled coil 1 (CC1) of Kinesin Heavy Chain (KHC) docks KLC-TPR domains, forming an autoinhibited 'shoulder'.
• Disrupting this interaction or SLiM binding dislocates the TPR shoulder, releasing motor domains.
• This promotes the transition from closed, inactive states to open states, facilitating microtubule binding.

Conclusions:

• Cargo-mediated dislocation of the TPR shoulder is a critical initial step in Kinesin-1 activation.
• This mechanism allosterically links cargo binding to motor domain dynamics and microtubule association.
• The findings reveal how cargo adaptors control Kinesin-1 activity for transport.