Luc Henry

Name

Name: Luc Henry
Nationality: Swiss

Laboratory of Protein Engineering
EPFL SB ISIC LIP1
BCH 4304 (Bât. BCH)
CH-1015 Lausanne
Switzerland

Contact details:
luc.henry@epfl.ch
+41 21 69 39 894

Biosketch

Luc Henry was born in Switzerland and studied biological chemistry in Lausanne (Switzerland), Uppsala (Sweden) and Oxford (UK), earning a M. Sc. in biological chemistry from the Ecole Polytechnique Fédérale de Lausanne (EPFL) in 2007. He then spent four  years as a DPhil student in the laboratory of Prof. Christopher J. Schofield at the University of Oxford, working on the enzymology of thienamycin and carnitine biosynthesis. He recently completed his doctoral studies and has returned to Lausanne to carry out postdoctoral work with Kai Johnsson. His scientific interests lie in the development of chemical tools to study biological systems.

In addition to organic chemistry and protein science, Luc has acquired experience in cell biology and cancer immunology. His interests are broadly distributed around the field of chemical biology and include natural products biosynthesis, human and bacterial metabolism, as well as many aspects of cell biology and cancer. His technical expertise includes organic synthesis, molecular biology, protein purification and crystallography, enzymology, analytical chemistry, tissue culture, histology, fluorescence microscopy amongst others.

Luc Henry is primarily based at the EPFL (link) but has spent a part of his fellowship in the laboratory of Prof. Nils Johnsson at the Institute of Molecular Genetic and Cell Biology of the University of Ulm, to learn Yeast-based genetics and other yeast-related methodologies. His SphingoNet project is entitled “Development of a novel drug target-profiling platform in yeast” (link).

When he is not in a laboratory, Luc is climbing or skiing down mountains, reading books or traveling to some exotic places. He is particularly interested in bioethics and the impact of biosciences on society, 20th century European novelists, and Middle Eastern cultures.

Project title: “Development of a novel drug target-profiling platform in yeast”

Project summary:

In most cases, a drug has an effect on the organism via its interaction with a specific human protein. However, there are examples of molecules used in the clinic for which the exact mode of action is still unknown. In addition, some drugs have a well-characterized mode of action but also show undesirable side effects of unknown origin. The identification of the human proteins interacting with a given molecule could potentially shed light on these two obscure points of pharmacology.

The aim of this project is to engineer yeast as a platform for the detection of small molecule-protein interactions. Our strategy will combine the SNAP self-labeling protein technology with a split-ubiquitin sensor. We will be screening small molecules of interest against human mRNA libraries in budding yeast (Saccharomyces cerevisiae) and this new approach is expected to expand the cellular target space of a previously described methodology based on a Y3H screen (Chidley et al 2011 Nat Chem Biol 7, 375), from strictly nuclear to cytosolic or membrane localization.

The SNAP technology was developed in the laboratory of Kai Johnsson and allows the covalent attachment of a small molecule ligand of interest (in yellow in Fig.1) to an engineered protein. The ligand contains three moieties: a benzylguanine (BG) functionality, which is the reactive group towards the engineered O6-alkylguanine-DNA alkyltransferase (SNAP), a linker that is usually a polyethylene glycol (PEG) moiety of given length, and a small molecule of interest, which can potentially be any drug.

Figure 1.The split-ubiquitin protein complementation assay is based on two protein fragments, NUb (35 amino acids) and CUb (42 amino acids), which reassemble into a functional (properly folded) ubiquitin protein when brought in close proximity. Proteins that are fused to the C-terminus of ubiquitin are cleaved off by ubiquitin-specific proteases upon reassembly (UbSP in Fig. 1).

Figure 1. General outline for the cytosolic version of the screen (adapted from Stynen et al. 2012 Microbiol. Mol. Biol. Rev. 76 331-382).

In Saccharomyces cerevisiae, the fate of a fusion reporter protein after proteolytic cleavage from ubiquitin C-terminus depends on the N-terminal amino acids (or “N-end rule”) and allows to choose between degradation or stabilization. Various selection strategies can be applied to select for interactions, depending on the polypeptide fused to the C-terminal fragment. One possible example is a screen in which cell survival depends on 5-FOA resistance upon loss of orotidine monophosphate decarboxylase activity through URA3 degradation (Fig.1).

This project is supervised by Prof. Kai Johnsson (link) and performed by Luc Henry (link) at the EPFL, Switzerland (link).

Supervisors

Kai Johnsson (EPFL Lausanne, Switzerland)
Nils Johnsson (University of Ulm, Germany)

Biosketch 1st scientific supervisor:

Kai Johnsson is a faculty member at the Institute of Chemical Sciences and Engineering (ISIC) of the Ecole Polytechnique Fédérale de Lausanne (EPFL), Switzerland. His laboratory is interested in protein engineering, and in particular in the development of tools to study and manipulate the biological function of proteins and small molecules in vivo and in vitro. Kai Johnsson is the co-director of the National Centre of Competence in Research (NCCR) «Chemical Biology – Visualisation and Control of Biological Processes Using Chemistry». He is an Associate Editor of ACS Chemical Biology, member of the editorial board of Chemistry & Biology, member of the advisory board of Chemical Society Reviews and Member of Faculty of 1000. He is co-founder of Covalys Biosciences, a company based on protein labeling technologies developed in his laboratory and now available through New England BioLabs. He received the EPFL Prix APLE for the invention of the year 2003.Two SPHINGONET projects are carried out under his supervision: “Development of a novel drug target-profiling platform in yeast” (link) and “Development and application of semi-synthetic sphingolipid sensors” (link)