Jan Steyaert

Publications

• Structure and flexibility of the endosomal Vps34 complex reveals the basis of its function on membranes Rostislavleva K* Soler N* Ohashi Y Zhang L Pardon E Burke J Masson G Johnson C Steyaert J Ktistakis N Williams R SCIENCE, 350, aac7365, 2015

• Jan Steyaert Lab Research focus Publications Job openings News Research focus Nanobody-enabled Structural Biology Published work of the Steyaert lab (see www.steyaertlab.eu for all details) established that the antigen binding fragments of Camelid heavy chain only antibodies - known as Nanobodies (Nbs)- constitute unique research tools in structural biology. By rigidifying flexible regions and obscuring aggregative surfaces, Nanobody complexes warrant conformationally uniform samples that are key to protein structure determination by X-ray crystallography or cryo-EM. We make and use nanobodies to investigate enzymes, membrane proteins and protein complexes that are involved in signal transduction. We focus on conformationally complex systems that have been resistant to structural investigation by conventional methods. Locking GPCR conformational states. The active-state conformations of G Protein Coupled Receptors (GPCRs) are unstable in the absence of specific cytosolic signaling partners representing key challenges for structural biology. We developed conformational Nanobodies against the β2 adrenergic receptor, the muscarinic acetylcholine receptor and the μ-opoid receptor that exhibit G protein-like behavior, and obtained the first agonist-bound, active-state crystal structures of these receptor●Nb complexes. Stabilizing transient signaling complexes. We developed nanobodies that stabilize the β2AR●Gs complex and others that bind to Vps34 complex II. These antibodies were instrumental for obtaining crystal structures of these key transient multiprotein assemblies, providing the first structural view on GPCR transmembrane signaling and on the regulation of autophagy, respectively. Unveiling conformational states of membrane transporters and ion channels. Functional understanding of membrane transporters and ion channels requires the structural characterization of different conformational states. Our lab produces Nanobodies to lock and solve the structures of key functional conformations of several transporters and ion channels by X-ray crystallography. Investigating the mechanism and regulation of complex GTPases. Guanine nucleotide binding proteins are regulatory hubs in nearly all cellular processes. While the small GTPases of the Ras superfamily have been relatively well characterized, the mechanism of complex multi-domain GTPases is much less established. The Versées lab studies the mechanism and regulation of particular complex GTPases that are implicated in bacterial virulence and persistence or have been linked to Parkinson disease and epilepsy. Founding ConFoTherapeutics. We transferred know-how and IP to ConFo Therapeutics, a new spin off company that exploits the conformational complexity of therapeutic targets for better drug discovery. top Publications Skywalker-TBC1D24 has a lipid-binding pocket mutated in epilepsy and required for synaptic function Fischer B* Lüthy K* Paesmans J* De Koninck C Maes I Swerts J Kuenen S Uytterhoeven V Verstreken P* Versées W* NATURE STRUCTURAL & MOLECULAR BIOLOGY, 23, 965-973, 2016 * These authors contributed equally Structural insights into micro-opioid receptor activation Huang W* Manglik A* Venkatakrishnan A Laeremans T Feinberg E Sanborn A Kato H Livingston K Thorsen T Kling R Granier S Gmeiner P Husbands S Traynor J Weis W Steyaert J Dror R Kobilka B NATURE, 524, 315-21, 2015

• Skywalker-TBC1D24 has a lipid-binding pocket mutated in epilepsy and required for synaptic function Fischer B* Lüthy K* Paesmans J* De Koninck C Maes I Swerts J Kuenen S Uytterhoeven V Verstreken P* Versées W* NATURE STRUCTURAL & MOLECULAR BIOLOGY, 23, 965-973, 2016

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