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A holistic study of S-acylation: function, regulation, and dynamics

English title A holistic study of S-acylation: function, regulation, and dynamics
Applicant van der Goot Gisou
Number 192608
Funding scheme Project funding (Div. I-III)
Research institution Global Health Institute EPFL SV-DO
Institution of higher education EPF Lausanne - EPFL
Main discipline Cellular Biology, Cytology
Start/End 01.07.2020 - 30.06.2024
Approved amount 1'224'000.00
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All Disciplines (4)

Discipline
Cellular Biology, Cytology
Biochemistry
Biophysics
Molecular Biology

Keywords (6)

acyl protein thioesterase; membrane proteins; membrane biology; membrane trafficking; palmitoylation; DHHC

Lay Summary (French)

Lead
Approche holistique de l'acylation des protéine
Lay summary

Une cellule biologique est une structure quasiment autonome, qui avec quelques ingrédients pris dans le milieu qui l’entoure, peut vivre et se multiplier. Ceci requiert une pléthore d’activités comme fabriquer des molécules qui la compose, dupliquer l’ADN quand elle se divise, réagir à son environnement pour survivre ou remplir sa fonction. Tout ceci est en grande partie exécuté par des protéines. Celles-ci doivent fonctionner de manière très bien contrôler dans le temps et dans l’espace. L’organisation spatiale au sein d’une cellule est largement orchestrée par des membranes lipidiques : la membrane plasmique qui sépare la cellule du milieu extérieur, les membranes qui entoure des organelles. Une modification chimique des protéines, qui consiste à leur attaché un lipide, contribue à la coordination spatio-temporelle des protéines. Elle est nommée S-acylation. Ce mécanisme est peu compris bien qu’essentiel. Le but de ce projet est d’avoir une meilleure compréhension de la S-acylation qui touche 10 à 20% de toutes les protéines exprimées chez l’humain.

La S-acylation est assuré par des enzymes spécifiques. Il en existe 23 dans le génome humain. Le fonctionnement et la spécificité de ces enzymes n’est pas connue. La S-acylation est réversible, c’est-à-dire qu’une autre série d’enzyme, les acylthioesterases, ont pour rôle d’enlever le lipide de protéines. La S-acylation-deacylation agit donc comme un interrupteur moléculaire permettant d’activer ou de désactivé une protéine. L’étude de ces différentes enzymes, de leur inter connectivité et de leur régulation est au cœur de ce projet.

Direct link to Lay Summary Last update: 11.12.2020

Responsible applicant and co-applicants

Employees

Abstract

Biological membranes are not only the physical walls surrounding cells and many intracellular compartments, but they are also essential to proper cell functioning because they ensure exquisite compartmentalization of biological processes and chemical reactions. While a wealth of information is available on cellular signaling pathways and biochemical reactions, how proteins are brought to the right place at the right time, often in the vicinity of membranes, is rarely understood at the molecular level. The spatiotemporal control of proteins is largely under the control of post-translational modifications. One of these stands out as particularly suitable for regulating protein-membrane interactions, which is S-acylation. It is the only reversible lipid modification, and can thus act as an on/off switch for proteins, along with phosphorylation or methylation. S-Acylation is the fourth most abundant reversible post-translational modification and appears to affect ˜20% of the human proteome, yet it is poorly characterized because a lack of suitable tools for studying it has left it mostly unnoticed. Recent methodological developments to detect S-acylation have greatly enhanced the interest in this modification and have revealed its major physiological importance, in that it affects metabolism, immunity, and brain and cardiac function, to name just a few.Despite major progress, our understanding of the S-acyltransferases (which add acyl groups), the protein deacylases (which remove acyl groups), and the mechanistic consequences of S-acylation are still rudimentary.We herein propose a holistic approach to S-acylation, aimed at understanding its role in organizing, shaping, and functionalizing membrane structures, around 4 major aims:1.Analyzing the spatiotemporal control of S-acyltransferases2.Understanding the consequences of S-acylation by analyzing selected ER membrane proteins3.Analyzing the spatiotemporal control of deacylating enzymes 4.Analyzing of the interconnectedness of acylating and deacylating enzymes and their respective targets through mathematical modeling of S-acylationOur pioneering work in S-acylation over the last decade puts us in a unique position to carry out this project successfully. We have mastered the various methods available world-wide to study this lipid modification, developing some of them ourselves. We have a long-standing interest in membrane biology, trafficking, and signaling that allows us to address the physiological consequences of the post-translational modification of our proteins of interest. Additionally, we have a broad approach to studying S-acylation, examining the acyltransferases, the deacylases, and the target proteins, both individually and in an integrated manner, with an interest spanning different scales from the atomic structure to the cell to the tissue. We tackle important unsolved questions from a variety of different angles and have established long standing collaborations at EPFL to complement our own expertise: Prof Vassily Hatzimanikatis, expert in biochemical engineering and modeling, and Prof. Matteo Dal Peraro, expert in molecular dynamics simulations and protein structure.
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