Uncovering the molecular effects of the tubulin code and their impact on organism-wide functions

Introduction

Microtubules (MT) are core components of the eukaryotic cytoskeleton with essential roles in cell division, cell shape, intracellular transport, and motility. Despite their functional divergence, MTs have highly conserved structures made from almost identical molecular building blocks – tubulin proteins. A variety of posttranslational modifications (PTMs) diversifies these building blocks, which is thought to control most of the properties and functions of the MT cytoskeleton, a concept referred to as the ‘tubulin code’.

Importance of Tubulin PTMs

While they appear to have subtle effects at the molecular level, tubulin PTMs are essential for maintaining cellular functions of MTs over large spatial and temporal scales. Yet, a comprehensive knowledge of the principles of the tubulin code, connecting its functions across the molecular, cellular, and organismal levels, is almost entirely lacking.

Project Objectives

Our project aims to obtain a novel molecular and mechanistic understanding of how tubulin PTMs control long-term cellular function and homeostasis. Our unique approach bridges all relevant scales of biology and relies on a synergy between our powerful experimental models and expertise in:

• Biochemistry
• Structural biology
• Single-molecule assays
• Systems biophysics
• Cell biology
• Physiology

Specific Goals

Specifically, we will:

1. Determine how different tubulin PTMs affect biophysical and structural properties of MTs and their interactions with associated proteins.
2. Define the impact of tubulin PTMs on overall MT cytoskeleton behavior and the resulting physiological implications in neurons.
3. Combine zebrafish and mouse models and develop a novel fish model for lifelong in-vivo imaging to determine how the tubulin PTMs control lifelong MT-based functions.

Expected Outcomes

Our work will define the importance of tubulin PTMs by revealing their critical molecular functions over the lifetime of an organism. The project has the potential to substantially change our perception of the cytoskeleton’s role in homeostasis and disease.