Mechanisms of protein SUMOylation and its functional consequences

Introduction

Protein post-translational modification with small ubiquitin-like modifiers (SUMO1, -2, and -3), also known as SUMOylation, targets a third of human proteins, is essential for organisms from yeast to humans, and has strong links to cancer and neurodegeneration.

SUMOylation and E3 Ligases

Like ubiquitylation, to which it is related, SUMOylation typically depends on the action of enzymes called E3 ligases, which help determine substrate specificity and the exact signal that is produced.

However, while for ubiquitylation several hundred E3s are known, no more than two dozen SUMO-specific E3s have been described and only four characterized structurally in a way that reveals their mechanism.

Intriguingly, the SUMO E3 ligase activity keeps being detected in proteins that are unrelated to each other and sometimes can be mapped to apparent disordered regions.

Project Objectives

In the first part of this project, I will explore the poorly charted territory of SUMO writing by elucidating the structure and mechanism of some known SUMO E3 ligases for which the mechanism is unclear.

This analysis will serve as a stepping stone to proposing computational, chemical biology, and structural biology approaches to identifying and characterizing new SUMO E3s.

Investigating SUMOylation Consequences

In the second part, I will investigate downstream consequences of SUMOylation. Following attachment to a protein substrate, SUMOylation is thought to function as a molecular glue by promoting the formation of protein complexes with specific SUMO readers, but detailed structural and biochemical information is lacking for any of such putative assemblies.

To address this topic, I will develop strategies to identify and characterize SUMO-dependent complexes.

Broader Implications

The new tools, approaches, and knowledge about SUMO writing and reading will be broadly applicable to pathways regulated by SUMOylation, allowing their understanding in molecular and mechanistic terms.

The study will also explore general concepts in protein evolution and the evolutionary emergence of signaling systems.