Autoinhibition and activation of myosin VI revealed by its cryo-EM structure

Area of Science:

• Molecular Biology
• Cell Biology
• Biochemistry

Background:

• Myosin VI is a unique molecular motor moving towards the minus end of actin filaments.
• Its activity is crucial for cellular functions and its dysregulation is linked to genetic diseases like deafness and cardiomyopathy.
• The precise mechanisms governing myosin VI activity regulation remain largely unknown.

Purpose of the Study:

• To elucidate the molecular mechanisms regulating myosin VI activity.
• To determine the high-resolution structure of autoinhibited myosin VI.
• To understand how cargo binding influences myosin VI motor function.

Main Methods:

• High-resolution cryo-electron microscopy (cryo-EM) to determine the structure of myosin VI.
• Biochemical assays to assess ATPase activity and cargo binding interactions.
• Structural analysis to identify key regulatory interfaces.

Main Results:

• The autoinhibited structure of myosin VI is compact and monomeric, with head and tail domains interacting extensively.
• An elongated single-α-helix region, termed a "spine," mediates these inhibitory interactions.
• This autoinhibited conformation blocks cargo binding sites and suppresses ATPase activity.
• Cargo adaptors, such as GIPC, disrupt these inhibitory interactions, leading to motor activation.
• The structure provides a basis for understanding disease-associated mutations in myosin VI.

Conclusions:

• Myosin VI is regulated by an autoinhibited state mediated by intramolecular interactions.
• Cargo binding adaptors play a critical role in activating myosin VI motor function.
• The findings offer insights into the regulation of other myosin motors, including myosin VII and X.