Structural basis for cytoplasmic dynein-1 regulation by Lis1

Area of Science:

• Molecular Biology
• Cell Biology
• Structural Biology

Background:

• The lissencephaly 1 gene (LIS1) is implicated in the neurodevelopmental disorder lissencephaly.
• The Lis1 protein is a vital regulator of cytoplasmic dynein-1, a critical microtubule motor.
• Lis1 directly interacts with dynein's motor domain, influencing its mechanochemistry and function.

Purpose of the Study:

• To determine the high-resolution structure of the yeast dynein-Lis1 complex.
• To elucidate the molecular details of the interactions between dynein and Lis1.
• To understand the functional significance of these interactions for dynein activity and regulation.

Main Methods:

• X-ray crystallography was employed to obtain a 3.1 Å resolution structure of the yeast dynein-Lis1 complex.
• Structure-guided mutagenesis was performed on both Lis1 and dynein proteins.
• Functional assays were used to assess the impact of mutations on dynein complex formation and activity.

Main Results:

• The study presents the first high-resolution structure of the yeast dynein-Lis1 complex, revealing detailed molecular contacts.
• Key interactions between dynein and Lis1, as well as within Lis1's ß-propellers, were identified.
• Structure-guided mutations disrupted these contacts, impairing Lis1's ability to form active human dynein complexes and regulate yeast dynein function.

Conclusions:

• The high-resolution structure provides critical insights into the mechanism of Lis1-mediated dynein regulation.
• The identified contacts are essential for Lis1's role in forming fully active dynein complexes.
• This work advances our understanding of dynein motor function and its regulation, relevant to neurodevelopmental disorders.