Regulation of Microtubule Disassembly by Spatially Heterogeneous Patterns of Acetylation

Abstract Microtubules (MTs) are bio-polymers, composed of tubulin proteins, involved in several functions such as cell division, transport of cargoes within cells, maintaining cellular structures etc. Their kinetics are often affected by chemical modifications on the filament known as Post Translational Modifications (PTMs). Acetylation is a PTM which occurs on the luminal surface of the MT lattice and has been observed to reduce the lateral interaction between tubulins on adjacent protofilaments. Depending on the properties of the acetylase enzyme α TAT1 and the structural features of MTs, the patterns of acetylation formed on MTs are observed to be quite diverse. In this study, we present a multi-protofilament model with spatially heterogenous patterns of acetylation, and investigate how the local kinetic differences arising from heterogeneity affect the global kinetics of MT filaments. From the computational study we conclude that a filament with spatially uniform acetylation is least stable against disassembly, while ones with more clustered acetylation patterns may provide better resistance against disassembly. The increase in disassembly times for clustered pattern as compared to uniform pattern can be upto fifty percent for identical amounts of acetylation. Given that acetylated MTs affect several cellular functions as well as diseases such as cancer, our study indicates that spatial patterns of acetylation need to be focussed on, apart from the overall amount of acetylation. Author Summary Microtubules (MTs) form a crucial part of the cytoskeletal machinery which regulates several cellular processes. The basic building block of MTs are tubulin proteins. These proteins assemble in lateral and longitudinal directions to form a hollow cylindrical structure of a MT. There are chemical modifications on tubulin, known as Post Translational Modifications (PTMs), which affect the stability and dynamics of MT filaments. We computationally study how one such PTM, namely acetylation, affects the kinetics of disassembly of a MT filament. We propose a model which incorporates spatially heterogeneous patterns of acetylation on MT filament and study how they may regulate the disassembly times and velocities, a factor hitherto unexplored in studies. We conclude that there are significant differences of disassembly velocities and their fluctuations depending on the differnces in spatial patterns of acetylation.