Schulte lab - About us
Our research aims to increase the understanding of basic pharmacology and underlying mechanisms of signal transduction and signaling specificity mediated by the Class Frizzled (FZD) receptors.
The class F of G protein-coupled receptors (GPCRs) consists of ten Frizzleds (FZD1-10) and Smoothened (SMO). The FZDs are - among other ligands - activated by 19 mammalian WNTs, a group of secreted lipoglycoproteins with an important role in embryonic development, stem cell regulation and human diseases, such as cancer. In the Schulte lab, we investigate how ligands activate FZDs in order to initiate intracellular changes. In this effort, we focus on ligand-receptor interaction, ligand-induced conformational changes in the receptor and aspects of conformational selection determining which downstream signaling pathways are activated. Thereby we hope to provide better insight into WNT-FZD binding mechanisms and selectivity and how intracellular signaling is initiated and specified by the individual FZD paralogues.
During the recent years, we have developed expertise in the use and design of genetically encoded biosensors that monitor ligand binding to FZDs, FZD conformational dynamics, FZD-effector binding and downstream effector activation. Furthermore, we combine these live cell assessments of the most upstream events of WNT-induced effects with in silico approaches such as molecular dynamics simulations and computational modelling to provide mechanistic insight into receptor activation and receptor complex dynamics on a molecular level.
One of the most important concepts that we have developed and that presents an important contribution to the field is the idea that FZDs are - similar to other GPCR – molecular machines that are defined by a structural flexibility and dynamics. Appreciation of this intrinsic flexibility is the basis for understanding receptor activation, receptor-mediated signal initiation and for targeting FZDs for therapy. Several important contributions from the Schulte lab have contributed to understand this central phenomenon (Wright and Kozielewicz et al. 2019; Kozielewicz et al. 2020; Turku et al. 2021; Kowalski-Jahn and Schihada et al. 2021; Schihada et al. 2021).
Our goal is to understand the complexity of WNT-induced events that determine the kinetics and nature of WNT signaling pathways governing embryonic development and tissue homeostasis. Since deregulated WNT signaling results in devastating diseases exemplified by many different and common forms of tumors (e g breast, intestinal, pancreatic cancer), bone disease, fibrosis and neurological disorders, we are convinced that targeting FZDs pharmacologically will open exciting strategies for the therapy of severe diseases.
Understanding how FZDs mediate WNT signaling to drive proliferation in a tumor or in a fibrotic tissue will allow us to design drugs that interfere with this message for therapeutic use. Our lab has shown for the first time that FZDs can be pharmacologically targeted by small molecule drugs (Kozielewicz et al. 2020) and we are currently developing this strategy to find drug-like compounds for anti-cancer treatment.
The computer simulation shows the interaction between FZD6 (white) and the small drug-like molecule SAG13 (purple).
The recent advances in our understanding of the details of FZD activation have been possible because of the development of biophysical assays that are suitable to dissect mechanistic aspects of signaling in an unprecedented manner. Furthermore, these assays are building the technological basis for drug screening efforts, which will explore the chemical matter on the quest for new drugs to treat cancer and other devastating human disorders.
References
Wright SC, Kozielewicz P, Kowalski-Jahn M, Petersen J, Bowin CF, Slodkowicz G, Marti-Solano M, Rodríguez D, Hot B, Okashah N, Strakova K, Valnohova J, Babu MM, Lambert NA, Carlsson J, Schulte G. A conserved molecular switch in Class F receptors regulates receptor activation and pathway selection. Nat Commun. 2019 Feb 8;10(1):667. doi: 10.1038/s41467-019-08630-2. PMID: 30737406
Kozielewicz P, Turku A, Bowin CF, Petersen J, Valnohova J, Cañizal MCA, Ono Y, Inoue A, Hoffmann C, Schulte G. Structural insight into small molecule action on Frizzleds. Nat Commun. 2020 Jan 21;11(1):414. doi: 10.1038/s41467-019-14149-3. PMID: 31964872
Wesslowski J, Kozielewicz P, Wang X, Cui H, Schihada H, Kranz D, Karuna M P, Levkin P, Gross JC, Boutros M, Schulte G, Davidson G. eGFP-tagged Wnt-3a enables functional analysis of Wnt trafficking and signaling and kinetic assessment of Wnt binding to full-length Frizzled. J Biol Chem. 2020 Jun 26;295(26):8759-8774. doi: 10.1074/jbc.RA120.012892. Epub 2020 May 7. PMID: 32381507
Schihada H, Kowalski-Jahn M, Turku A, Schulte G. Deconvolution of WNT-induced Frizzled conformational dynamics with fluorescent biosensors. Biosens Bioelectron. 2021 Apr 1;177:112948. doi: 10.1016/j.bios.2020.112948. Epub 2020 Dec 30. PMID: 33486136
Kozielewicz P, Shekhani R, Moser S, Bowin CF, Wesslowski J, Davidson G, Schulte G. Quantitative Profiling of WNT-3A Binding to All Human Frizzled Paralogues in HEK293 Cells by NanoBiT/BRET Assessments. ACS Pharmacol Transl Sci. 2021 May 11;4(3):1235-1245. doi: 10.1021/acsptsci.1c00084. eCollection 2021 Jun 11. PMID: 34151213
Turku A, Schihada H, Kozielewicz P, Bowin CF, Schulte G. Residue 6.43 defines receptor function in class F GPCRs. Nat Commun. 2021 Jun 24;12(1):3919. doi: 10.1038/s41467-021-24004-z. PMID: 34168128
Xu L, Chen B, Schihada H, Wright SC, Turku A, Wu Y, Han GW, Kowalski-Jahn M, Kozielewicz P, Bowin CF, Zhang X, Li C, Bouvier M, Schulte G, Xu F. Cryo-EM structure of constitutively active human Frizzled 7 in complex with heterotrimeric Gs. Cell Res. 2021 Jul 8. doi: 10.1038/s41422-021-00525-6. Online ahead of print. PMID: 34239071
Kowalski-Jahn M, Schihada H, Turku A, Huber T, Sakmar TP, Schulte G. Frizzled BRET sensors based on bioorthogonal labeling of unnatural amino acids reveal WNT-induced dynamics of the cysteine-rich domain. Sci Adv. 2021 Nov 12;7(46):eabj7917. doi: 10.1126/sciadv.abj7917. Epub 2021 Nov 10. PMID: 34757789
Group members
Current members
- Gunnar Schulte
- Pawel Kozielewicz, postdoc
- Lukas Graetz, postdoc
- Magdalena Scharf, postdoc
- Rawan Shekhani (PhD student)
- Julien Bous, postdoc
- Julia Kinsolving (PhD student)
- Remy Sounier (remsou), guest researcher from the IGF in Montpellier.
- Jan Voss (janvos), postdoc lab
- Björn Forsberg, postdoc
Alumni
- Maria Kowalski-Jahn, postdoc
- Ainoleena Turku, postdoc
- Shane Wright, postdoc
- Elisa Arthofer, PhD
- Fredrik Brand, Master's student from the Lausitz University of Applied Sciences, Germany
- Jenny Dahlström, Med kand, master's student
- Jacomijn Dijksterhuis, PhD
- Carina Halleskog, PhD
- Rober Helbig, PhD, postdoctoral fellow
- Belma Hot, PhD
- Michaela Kilander, PhD
- Natália Assaife Lopes, PhD student, Faculty of Medicine, University of Lisbon, Portugal
- Tobias Ludwig, Student from the Free University of Berlin, Germany
- Javier Becerril Ortega, PhD, postdoctoral fellow
- Julian Petersen, PhD
- Tilman Polonio, Student from Heidelberg University, Germany
- Jana Valnohova, PhD
- Alice Weithäuser, Master's student from the Free University of Berlin, Germany
- Carl Fredrik Bowin (PhD student)
- Hannes Schihada, postdoc
Research support - past and present
- Alex & Eva Wallström Stiftelse
- Cancerfonden
- Emil och Wera Cornells Stiftelse
- EUbOPEN
- Fernströms Stiftelsen
- FP7 Marie Skłodowska-Curie actions
- GACR (Czech Science Foundation)
- Hjärnfonden
- Jeanssons Stiftelse
- Karolinska Institutet
- KI/NIH Joint PhD
- KID
- Knut & Alice Wallenberg Stiftelse
- Max & Edith Follins Stiftelse
- Novonordiskfonden
- Signe & Olof Wallenius Stiftelse
- Signhild Engkvists Stiftelse
- Socialstyrelsen
- Stiftelsen Olle Engkvist Byggmästare
- STINT
- Tore Nilson Stiftelse
- Vetenskapsrådet
- Wenner-Gren Foundation
- Åhlén Stiftelse
- Åke Wiberg Stiftelse