BioParadigms
Hediger Membrane Transport Discovery Lab

Prof. Dr. Matthias A. Hediger

Membrane Transport Discovery Lab
Head of the Lab

Department of Nephrology and Hypertension
Inselspital, University of Bern
Kinderklinik, Office D845, Freiburgstrasse 15
CH-3010 Bern
Switzerland

Matthias Hediger, Department of Nephrology and Hypertension, University of Bern

matthias.hediger@ibmm.unibe.ch
Phone: +41 31 632 94 39

CV and publication list

Research Goals and Activities

Research arising from the Hediger group has historically focused on the functional characterization of clinically important membrane transporters and ion channels using a variety of methodologies such as electrophysiology, classical transport studies, microscale thermophoresis, structure function analysis, advanced imaging technologies and bioinformatics. Over the past 25 years, this work has revealed the mechanistic foundations for transporters of iron (SLC11A2), vitamin C (SVCT1 and SVCT2), urea (SLC14A2), citrate (SLC13A2), glutamate (SLC1A1), dibasic amino acids (SLC3A1) and peptides (SLC15A1), as well as the epithelial calcium channels TRPV5 and TRPV6. Additional work has been devoted to the mechanisms of store-operated calcium entry by the Stim-Orai pathway. Most recent efforts exploit the combination of knowledge from atomic structures of these proteins with computational modelling, molecular dynamics (MD) simulations, site-directed mutagenesis and compound screening. This approach has unveiled novel insight into the translocation and gating mechanisms of these proteins and thereby accelerates the development of potential therapeutic modulators for the treatment of human diseases.

Current projects

  1. The new SLC Atlas
  2. Structure, function and therapeutic implications of the SLC11A2/DMT1 iron transporter; role in hemochromatosis
  3. SLC39/ZIP metal ion transporters and in pathologies (e.g. osteoarthritis, hypertension)
  4. Calcium channels (Orai/STIM/TRPV6) in health and disease
  5. Role of amino acid transporters in colorectal cancer progression
  6. Mitochondrial SLC solute carriers and their role in energy metabolism and tumor progression
  7. Investigation of the biology of the endosomal peptide/histidine transporter SLC15A4
  8. Glial glutamate transporters (SLC1A2/GLT1)

Other activities

  1. Establishment of NCCR TransCure
  2. Conference organization
  3. SLC mini-review series and BioParadigms website

Current Projects

1. The new SLC Atlas

Membrane Transport Discovery Lab (Group leader Prof. em. Matthias A. Hediger) (https://www.bioparadigms.org/) — Our research focuses on membrane transport proteins and ion channels that play key roles in vital physiological processes in the human body. These proteins are the gatekeepers in membranes of cells and organelles and their dysfunction contributes to the pathogenesis of a wide variety of human diseases. Our emphasis is to develop unique therapeutic treatment strategies and precision medicine tools based on new knowledge obtained from these proteins. Recently, our group has undertaken the identification and classification of Solute Carrier (SLC) transporter proteins in mammalian proteomes (see Figure showing a circular dendrogram of the clustering of all known human transmembrane transporter of the SLC solute carrier series). By synthesizing information from various publicly available databases and scientific literature, we have recently identified ~150 putative new SLCs from human, of which ~25 have known transport function. SLC transporter play important roles in the maintenance of biological barriers in brain, kidney, intestine and many other organs, as well as intracellular organelles. Additionally, currently around 40% of SLCs are orphans, i.e. their physiological substrates and function are still not known. Compared to their physiological importance, SLCs are still relatively unexploited as therapeutic targets, and their characterization can potentially open the way for novel personalized therapeutic applications. Ref.: César-Razquin A, et al., Cell. 2015, 162(3):478-87.

2. Structure, function and therapeutic implications of the SLC11A2/DMT1 iron transporter; role in hemochromatosis

After the molecular discovery of the divalent metal ion transporter by our group (Nature. 1997, 388:482-8), Raimund Dutzler, as part of the NCCR TransCure iron project, reported the 3D structure of DMT1/SLC11A2 from Staphylococcus capitis (ScaDMT), unveiling it as a LeuT-fold transporter. As a follow-up, we employed molecular dynamics simulations and site-directed mutagenesis and discovered a novel H+ transfer mechanism in DMT1. Our molecular dynamics simulations provided first insight into how H+-translocation through E193 is allosterically linked to intracellular gating, revealing a novel H+-coupling mechanism that is distinct from that of other H+-transporters (Sci Rep. 2017, 7:6194). The mechanistic base of the inhibition of DMT1 has recently been elucidated for bis-isothiourea substituted compounds in collaboration with the groups of Raimund Dutzler (University of Zürich) and Jean-Louis Reymond (University of Bern) and our paper on this topic has now just been accepted by eLife (Elife. 2019 Dec 5;8. pii: e51913, see figure).

3. SLC39/ZIP metal ion transporters and in pathologies (e.g. osteoarthritis, hypertension)

SLC39/ZIP metal ion transporters and in pathologies: A combination of in silico and in vitro techniques involving structural modeling, mutagenesis and functional characterization was employed to unravel the structural elements of pH sensitivity and substrate binding in the human zinc transporter SLC39A2 (ZIP2), thereby providing the first structural evidence for the previously observed pH and voltage modulation of ZIP2-mediated metal transport (J Biol Chem. 2019, 294:8046-8063). An inhibitor against the SLC39A8/ZIP8 zinc transporter has recently been generated and will be tested using an in vitro osteoarthritis cellular system, looking for beneficial disease treatment effects.

4. Calcium channels (Orai/STIM/TRPV6) in health and disease

A. TRPV6

TRP channels comprise a collection of 28 channels that are grouped into several subfamilies. The TRPV subfamily includes six members. The TRPV6 and TRPV5 channels are remarkably calcium-selective, making them unique within the TRP family and ideally suited as apical calcium entry mechanisms in absorptive tissues (J.-B. Peng, Y. Suzuki, G. Gyimesi & M. A. Hediger, 2018, see figure). As part of the activities of the NCCR TransCure network (see below), we have been working with the group of Jean-Louis Reymond to look for specific TRPV6 inhibitors. Our effort has led to the generation of the first inhibitor, cis-22a, that exhibits a remarkable specificity, with an IC50 value in the subnanomolar range (Angew Chem Int Ed Engl. 2015, 54:14748-52). Recent efforts have focused on studies of human TRPV6 mutants that exhibit reduced inhibition with cis-22a compared to wt. Interestingly, certain mutants of residues of the 2APB binding pocket also exhibited reduced inhibition by cis-22a. The 2015 “Angewandte Chemie” paper also included molecular docking calculations for cis-22a that our lab performed using an in-house created model of TRPV6 based on the previously published structure of TRPV1. Interestingly, the aforementioned co-crystallization shows that the inhibitor is precisely located where our previous docking studies of the Angew Chem paper had it predicted, thereby validating that our docking studies were correct. In collaboration with Jean-Louis Reymond and Christoph Romanin, we developed a novel photoswitchable inhibitor of TRPV6 that is expected to serve as a versatile tool compound to deepen our understanding of TRPV6 (ACS Med Chem Lett. 2019, 10:1341-1345). In addition, our first paper on capsaicin derivatives and their effects on TRPV1 and TRPV6 channel function has just been released (Bioorg Med Chem. 2019, 27:2893-2904).

B. Orai/STIM

Structure, function and pharmacology of Orai/STIM calcium channels: In year 2015, our laboratory got awarded a Swiss-Sinergia interdisciplinary research grant entitled “Store-operated calcium channels in health and disease”, together with Nicolas Demaurex (Cellular Physiologist, University of Geneva, Switzerland) and Martin Lochner, we therefore became engaged in numerous projects on SOCE and STIM. This work is just now beginning to yield publications, and the first couple of papers already came out, published in collaboration with Nicolas Demaurex (J Physiol. 2019, 597:561-582), as well as Christoph Romanin and Jean-Louis Reymond (Cell Calcium. 2019, 79:57-67).

5. Role of amino acid transporters in colorectal cancer progression

The figure on the right shows the role of amino acid transporters in mTOR activation, energy metabolism, nutritional stress and tumor progression (Trends Biochem Sci. 2018, 43(10):752-789). Our recent data reveal that oncogenic mutations boost amino acid delivery into colorectal cancer (CRC) cells via hippo-mediated upregulation of specific amino acid transporters (manuscript in preparation). Briefly, we investigated the impact of oncogenic and tumor suppressor mutations on the regulation of expression of amino acid transporters in CRC. We found that KRAS and BRAF oncogenic mutations present in different CRC subtypes upregulate the expression and functions of specific amino acid transporters. Our findings suggest that inhibiting amino acid transporters could represent a novel approach for personalized cancer treatment in KRAS/BRAF-mutant tumors.

6. Mitochondrial SLC solute carriers and their role in energy metabolism and tumor progression

This is recently initiated, Swiss Science Foundation-funded Sinergia project, that is being carried out in collaboration with Edmund Kunji, MRC Mitochondrial Biology Unit, Cambridge Biomedical Campus, UK and Martin Lochner (University of Bern). The goal is to investigate the role of Ca2+ flow across contact sites between the ER and mitochondrial membranes, especially in the context of Ca2+-regulated mitochondrial solute carriers, in regulating the bioenergetics of cells under healthy conditions and during metabolic reprogramming in cancer.

7. Investigation of the biology of the endosomal peptide/histidine transporter SLC15A4

The orphan endosomal peptide/histidine transporter SLC15A4 is currently being evaluated with respect to application to the treatment of autoimmune diseases such systemic lupus erythematosus (SLE) and inflammatory bowel disease (IBD). The SLC15 family includes four different members (SLC15A1-A4). SLC15A1 (intestinal PepT1) and SLC15A2 (renal PepT2) have previously been extensively studied by our laboratory (Nature. 1994, 368(6471):563-6). SLC15A3 and SLC15A4 have low sequence similarities to SLC15A1 and SLC15A2 and their substrate selectivity is thought to be restricted to histidine, certain oligopeptides and muramyl peptides that represent fragments of peptidoglycan from pathogens, e.g. the bacterial cell wall. SLC15A4 is a peptide/histidine transporter essential component of the inflammatory response system triggered by Toll-like receptors (TLR) pathway. Ligand binding and signaling of TLRs are modulated by the content of histidine and the pH inside the lysosomes (see Figure). The histidine level in lysosomes is thought to be maintained within a defined concentration range by SLC15A4 to warrant maximal functional efficiency of the lysosomal components, including TLR maturation and function. The absence of SLC15A4 leads to failure in the homeostasis of the lysosomal environment, which could explain the disruption of the TLR signaling pathway in SLC15A4-deficient cells. Additionally, SLC15A4 seems to be involved in the transport of the peptidoglycan-like NOD1 ligand, tri-DAP, and the NOD2 cognate ligand muramyl dipeptide (MDP) from lysosomes to the cytosol. Our goal is to generate SLC15A4 inhibitors as a therapeutic treatment strategy for SLE and IBD. Using microscale thermophoresis (MST), we have screened a diverse library of 1600 compounds and identified several hits that are currently being investigated.

8. Glial glutamate transporters (SLC1A2/GLT1)

Our recent collaboration with Rodan, Lance, Children’s Hospital, Harvard Medical School revealed novel glutamate transporter mutations that cause epilepsy via a dominant negative mechanism. We found that these mutations are localized in the trimerization domain of the glutamate transporter trimers (Ann Neurol. 2019, 85:921-926).

Other Activities

1. Establishment of NCCR TransCure

The National Centre of Competence in Research (NCCR) “TransCure” has been initiated and directed by Matthias Hediger starting in year 2010, with the main goal to accelerate the transformation of knowledge from basic research within the transporter/channel field into use. The leading house of this network is the University of Bern (www.nccr-transcure.ch/about-us, and it is currently ran by Hugues Abriel. Our network is composed of a dozen multidisciplinary scientific laboratories affiliated at Universities in Basel, Bern, Lausanne and Zürich. This team of Swiss academic experts are focused on cellular membrane transporter/channel research and emerging applications for the treatment of human diseases. Using TransCure's approach “from transport physiology to the identification of therapeutic targets” researchers are working collaboratively, combining a unique interdisciplinary skill-set that encompasses three major disciplines, referred to as “TransCure Trias”: Physiology/Medicine, Structural Biology and Medicinal Chemistry. The NCCR TransCure projects are expected to accelerate the development of therapeutic strategies, ultimately to improve human health.

2. Conference organization

Matthias Hediger has established two different international conference series to promote the transporter/ion channel field in the biomedical and pharmaceutical areas:

3. SLC mini-review series and BioParadigms website

There are currently 65 human transporter gene families belonging to the SLC (solute carrier) series and these families include 432 genes. Matthias Hediger serves as Special Advisor on SLCs to the HUGO Gene Nomenclature Committee (HGNC). The SLC tables are presented on the BioParadigms website.

Lab Members

Verena Frazao

Secretary
verena.frazao@dbmr.unibe.ch
+41 31 632 94 38

Dr. Bartłomiej Augustynek

Postdoc
bartlomiej.augustynek@dbmr.unibe.ch
+41 31 632 22 93

Dr. Rajesh Bhardwaj

Postdoc
rajesh.bhardwaj@dbmr.unibe.ch
+41 31 632 22 93

Dr. Benjamin Clémençon

Postdoc
benjamin.clemencon@dbmr.unibe.ch
+41 31 632 22 93

Dr. Gergely Gyimesi

Postdoc
gergely.gyimesi@dbmr.unibe.ch
+41 31 632 22 93

Dr. Palanivel Kandasamy

Postdoc
palanivel.kandasamy@dbmr.unibe.ch
+41 31 632 94 38

Dr. Jonai Pujol Giménez

Postdoc
jonai.pujol@dbmr.unibe.ch
+41 31 632 94 76

Damian Nydegger

PhD Student
damian.nydegger@dbmr.unibe.ch
+41 31 632 94 38

Jan Dernič

MSc Student
jan.dernic@students.unibe.ch
+41 31 632 22 93