Thursday, November 8, 2018

BISTRO - Shashank Jariwala

4:00 PM

2036 Palmer Commons

BISTRO is restricted to U-M Bioinformatics Graduate Program students and faculty.

"Understanding the dynamics of cytoskeletal proteins with molecular dynamics simulations."

Abstract

Microtubules and the kinesin family of motor proteins play a crucial role in the cytoskeleton of the cell, providing structural support as well as facilitating cellular transport, beating of cilia and flagella, and separation of chromosomes during the cell cycle. Results from studies of the unique biochemical and biophysical properties of microtubules in worms will be discussed. In brief, molecular dynamics (MD) simulations revealed that amino acid substitutions in worm tubulin lead to new secondary structure formation, and this structuring of tubulin-tubulin interacting residues changes the polymerization behavior. These results, complemented by in vitro experiments, improve our understanding of microtubule polymerization, which is central of the biological function of microtubules.
Preliminary results from simulations of the molecular motor protein KIF1A will also be discussed. KIF1A is a molecular motor of the kinesin-3 family of motor proteins, with primary function of anterograde transport of synaptic vesicle precursors along axonal microtubules. Recently, a number of disease-associated genetic variants and de novo mutations have been identified from clinical studies. These mutations have been linked to neurodevelopmental disorders including cognitive disability, spasticity, and cerebellar and optic nerve atrophy. The mechanism of how these mutations disrupt motor function is not understood. We characterized the dynamical effects of V8M mutation located on the motor domain of KIF1A. We observed significant changes in residue-residue interactions for three functionally important domains. First, V8M impacted residues involved in the power stroke, i.e., neck linker (NL), cover strand (CS), and β7, and suggest an unexpected output of enhanced NL docking. Second, differences in interactions between nucleotide coordinating residues indicate an impact on ATPase activity. Third, decreased interactions for residues interacting with the microtubule in α4, L11/switch-2, L13, and α6 suggest the V8M motor is slower and less processive, consistent with previous experimental work (Scarabelli et al 2015). Current efforts are focused on experimentally measuring the kinetic and motility properties of mutant motors. Our results demonstrate the allosteric effects of KIF1A neurological disease-associated mutations and help us better understand how mutations in kinesin motors can lead to neurodevelopmental disorders.