Proteins are essential components of all known organisms and are involved in practically every process of life. One of the great challenges for the life sciences in the post-genomic age is to read the function and interactions of proteins and to exploit this knowledge for therapy. Innovations in the field of automation and miniaturization enable us to gain new molecular insights into the function of proteins and explore novel therapeutic approaches.
Our organic-chemical and biological-synthetic biochip technology allows us to study protein interactions with highest throughput and to transform peptide-derived compounds into compact and highly affine binding molecules with optimized selectivity profiles.
Peptide Based Markers and Tools
Due to their comparably small size and superior binding properties, the peptide-based compounds - developed and manufactured by us - are both specific inhibitors as well as excellent protein labels. Our newly developed fluorescent probes unleash the full resolution potential of the latest high-end microscopy technologies and thereby help to gain new insights into cellular processes.
New Neuropharmacological Approaches
A subgroup of autoimmune neuropathies is caused by autoantibodies against critical nerve structures. Here the severity of the disease correlates with the antibody levels and neutralization or removal of antibodies leads to an immediate recovery of the patient. So far, however, only a small part of the existing autoantigens has been identified. In order to counter this great limitation of diagnostic and therapeutic possibilities, we use our array technology to identify new autoantigens on critical structures of the peripheral nerves.
Worldwide, more than 50 million people suffer from epilepsy and over 20 million people are diagnosed with schizophrenia. The therapeutic options for these serious and chronic diseases of the brain are limited and a significant proportion of patients show a poor response to treatment. γ-Aminobutyric acid type A receptors (GABAARs) are the main mediators of phasic and tonic inhibition in the human brain and an important neuropharmacological drug target. Currently used drugs have limited GABAAR subtype specificity and affect receptors across different brain regions and neuronal structures. This inherent lack of specificity causes severe side effects and drastically limits the effectiveness of the active ingredients. We envision a new form of GABAAR-based specific therapy to precisely target certain dysfunctional neural pathways. In particular, we explore GABAAR-associated proteins as a means of influencing disease-related protein complexes in certain brain regions as well as discrete neuronal pathways.
7.October 2020 Two Posters for Eureka!
Violetta Peck et al. and Markus Bayer et al. will present two posters summarizing their works at the international EUREKA! Symposium. Enjoy the talks and posters!
René Weyer has joined our lab as part of his master thesis in Biochemistry. He will define protein interaction profiles for kinases using microarrays and bioinformatics.
01.October 2020 Paraskevi Samara Erasmus Internship
We welcome Paraskevi Samara from the National and Kapodistrian University of Athens to our lab. She will use microarrays to explore the molecular mechanisms that underly the function of the inhibitory synapse.
1.September 2020 Open PhD Position
We are looking for a PhD student (link = https://www.uni-wuerzburg.de/rvz/aktuelles/jobs-karriere/stellenangebote/) highly motivated to identify and characterize new immune neuropathy autoantigens. The project will encompass the use of synthetic chemistry, biophysical characterisation of biomolecular binding interactions and modern automatization technologies.
23.June 2020 Sarah-Marie Buchmann Master Thesis
Sarah-Marie Buchmann has joined our lab for working on her Master Thesis in Biology. The topic of her Thesis is "On-Chip detection and profiling of anti SARS-nCOV2 antibodies: Human Milk Immunity and profiling of therapeutic antibodies"
8.June 2020 Rafael Worschech Master Thesis
Welcome Rafael! He joins our lab as part of his master thesis. Using high affinity, super-binding peptide (SBP) based fluorescent probes, he will explore the GABAA and glycine receptor subtype specificity of major gephyrin isoforms via high-end microscopy. Good luck!
29.May 2020 Gründl et al 2020
Congratulations to Marco Gründl and Stefan Gaubatz on their successful characterization of the interaction between YAP and Myb-MuvB (MMB) complex revealing its role in the proliferation of cardiomyocytes in Plos Biology (link = https://doi.org/10.1371/journal.pgen.1008818). Props to Clemens who contributed the YAP/MMB complex mapping.
30.April 2020 IZKF
Thank you very much to the IZKF (link = https://www.med.uni-wuerzburg.de/izkf/forschungsfoerderung/izkf-projektfoerderung/) for giving us the opportunity to realize the project with the goal to unravel the molecular pathogenesis of nodal and paranodal autoantibodies in Patients with auto-immune neuropathy. We are looking forward to the collaboration with Katrin Doppler and are very excited for the results to come.
30.April 2020 Langlhofer et al 2020
We are very pleased to see the work of Georg Langlhofer resolving the molecular pathology of a hereditary form of hyperekplexia being published in the Journal of Neuroscience (link = https://doi.org/10.1523/JNEUROSCI.2490-19.2020). We mapped and characterized syndapin I binding and contributed to show how the mutation leads to this type of startle disease. We are excited to move this further forward!
25. March 2020
The JMU provided 20.000 Euros "Start-up Funding" to support the preparation of our next research initiative.
Die JMU unterstützt die Vorbereitung unserer nächsten Forschungsinitiative mit 20.000 Euro "Start-up Funding" - Vielen Dank!
4.March 2020 Prieto-Garcia et al
Congratulations to Cristian Prieto-Garcia and Markus Diefenbacher on their recent work published in EMBO Molecular Medicine delineating the role of USP 28 in squamosa cell carcinoma (link = https://doi.org/10.15252/emmm.201911101). We are very glad of being able to have contributed to your work and look forward to future collaborations.
Violetta Peck has joined our lab for working on her medical Phd project. She as well was awarded a GSLS scholarship to characterize receptor-binding-profiles of native gephyrin from mouse-brain-lysates using our microarrays.
10 October 2019
Rico Petermann has joined our lab for working on his Master Thesis in Biology. The topic of his Master Thesis is “Molecular Basis Syndapin’s Interaction with Inhibitory Posts-Synaptic Proteins”.
26 June 2019
Vladimirs`new article is online. He introduces new strategies to modulate GABAergic signalling. Good job Vladimir! Link to publication
3 June 2019
See you at the ReceptorLight Symposium No.2 in Jena! Clemens, Noah, Vladimir & Hans will present their recent progress in profiling native proteins and developing fluorescent probes.
27 May 2019
Publication in Nature Genetics. The Kubicek lab identified MTHFD1, a folate pathway enzyme, as genetic and physical interactor of the important transcription regulator BRD4. Using our microarray technology we mapped the exact binding interface of the BRD4/MTHFD1 complex.
9 August 2018
David Baumstark and Rico Petermann decided to support us to further develop and apply our peptide microarray technology platform!
7 August 2018
Congratulations to Rochelle and Steven for their great work on the collybistin protein that was just accepted in Nature Communications! We identified an exclusive binding of collybistin to the GABAAR-α2-subunit. - Notably, the first report of a high-affinity protein interaction for both proteins. Based on these results Rochelle created knock-in mice and demonstrated that this interaction is critical for the correct targeting and stabilisation of distinct α2-containing GABAAR clusters. She found that interfering with this protein interaction resulted in spontaneous seizures during development, accompanied by early mortality. Surviving mice have increased anxiety-like behavior and EEG abnormalities that are responsive to α2-selective benzodiazepines, revealing a novel therapeutic potential for these compounds. Publication
30 June 2018
Daniel Otzen just published his recent insight into the mechanism of functional Amyloid Formation. Using our microarray-based approach we identified specific motifs that are implicated in amyloid formation. These could lay the foundation for development of peptide-based amyloid inhibitors. Publication
6 June 2018
Neuroscience conference in Schaffhausen, Switzerland. It was a great pleasure to the emerging mechanisms for inhibitory synapse plasticity! Shuang-Yan & Hans presented their plans how to use the microarray technology to gain molecular level insight into neurobiological processes.
2 May 2018
We welcome biomedicine student Elisa Speth and senior scientist Dr. Shuang-Yan Wang. Dr. Shuang-Yan Wang joined us from Prof. John Robinsons group in Zürich where he developed highly specific cyclic peptidomimetics antibiotics in close cooperation with Polyphor.
Schulte C and Maric HM. Expanding GABAAR pharmacology via receptor-associated proteins. Curr Opin Pharmacol, 56 (2021). Ahead of print
Bartling CRO, Jensen TMT, Henry SM, Colliander AL, Sereikaite V, Wenzler M, Jain P, Maric HM, Harpsøe K, Pedersen SW, Clemmensen LS, Haugaard-Kedström LM, Gloriam DE, Ho A, Strømgaard K. Targeting the APP-Mint2 Protein-Protein Interaction with a Peptide-Based Inhibitor Reduces Amyloid-β Formation. J Am Chem Soc. 2021 Jan 20;143(2):891-901. doi: 10.1021/jacs.0c10696.
Moreno-Yruela C, Bæk M, Vrsanova AE, Schulte C, Maric HM*, Olsen CA*. Hydroxamic acid-modified peptide microarrays for profiling isozyme-selective interactions and inhibition of histone deacetylases. Nat Commun. 2021 Jan 4;12(1):62. doi: 10.1038/s41467-020-20250-9.
(*shared corresponding authors)
Schulte C, Khayenko V, Nordblom NF, Tippel F, Peck V, Gupta AJ, Maric HM. High-throughput determination of protein affinities using unmodified peptide libraries in nanomolar scale. iScience. 2020 Dec 7;24(1):101898. doi: 10.1016/j.isci.2020.101898.
Gründl M, Walz S, Hauf L, Schwab M, Werner KM, Spahr S, Schulte C, Maric HM, Ade CP, Gaubatz S. Interaction of YAP with the Myb-MuvB (MMB) complex defines a transcriptional program to promote the proliferation of cardiomyocytes. PLoS Genet. 2020 May 29;16(5):e1008818. doi: 10.1371/journal.pgen.1008818.
Langlhofer G, Schaefer N, Maric HM, Keramidas A, Zhang Y, Baumann P, Blum R, Breitinger U, Strømgaard K, Schlosser A, Kessels MM, Koch D, Qualmann B, Breitinger HG, Lynch JW, Villmann C. A Novel Glycine Receptor Variant with Startle Disease Affects Syndapin I and Glycinergic Inhibition. J Neurosci. 2020 Jun 17;40(25):4954-4969. doi: 10.1523/JNEUROSCI.2490-19.2020.
Prieto-Garcia C, Hartmann O, Reissland M, Braun F, Fischer T, Walz S, Schülein-Völk C, Eilers U, Ade CP, Calzado MA, Orian A, Maric HM, Münch C, Rosenfeldt M, Eilers M, Diefenbacher ME. Maintaining protein stability of ∆Np63 via USP28 is required by squamous cancer cells. EMBO Mol Med. 2020 Apr 7;12(4):e11101. doi: 10.15252/emmm.201911101.
Sereikaite V, Fritzius T, Kasaragod VB, Bader N, Maric HM, Schindelin H, Bettler B, Strømgaard K. Targeting the γ-Aminobutyric Acid Type B Receptor Complex: Development of Inhibitors Targeting the K+ Channel Tetramerization Domain Containing Proteins/GABAB Receptor Protein-Protein Interaction. J Med Chem. 2019 Oct 10;62(19):8819-8830. doi: 10.1021/acs.jmedchem.9b01087.
Khayenko V, Maric HM. Targeting GABAAR-Associated Proteins: New Modulators, Labels and Concepts. Front Mol Neurosci. 2019 Jun 26;12:162. doi: 10.3389/fnmol.2019.00162.
Sdelci S, Rendeiro AF, Rathert P, You W, Lin JG, Ringler A, Hofstätter G, Moll HP, Gürtl B, Farlik M, Schick S, Klepsch F, Oldach M, Buphamalai P, Schischlik F, Májek P, Parapatics K, Schmidl C, Schuster M, Penz T, Buckley DL, Hudecz O, Imre R, Wang SY, Maric HM, Kralovics R, Bennett KL, Müller AC, Mechtler K, Menche J, Bradner JE, Winter GE, Klavins K, Casanova E, Bock C, Zuber J, Kubicek S. MTHFD1 interaction with BRD4 links folate metabolism to transcriptional regulation. Nat Genet. 2019 Jun;51(6):990-998. doi: 10.1038/s41588-019-0413-z.
Baluapuri A, Hofstetter J, Dudvarski Stankovic N, Endres T, Bhandare P, Vos SM, Adhikari B, Schwarz JD, Narain A, Vogt M, Wang SY, Düster R, Jung LA, Vanselow JT, Wiegering A, Geyer M, Maric HM, Gallant P, Walz S, Schlosser A, Cramer P, Eilers M, Wolf E. MYC Recruits SPT5 to RNA Polymerase II to Promote Processive Transcription Elongation. Mol Cell. 2019 May 16;74(4):674-687.e11. doi: 10.1016/j.molcel.2019.02.031.
Kasaragod VB, Hausrat TJ, Schaefer N, Kuhn M, Christensen NR, Tessmer I, Maric HM, Madsen KL, Sotriffer C, Villmann C, Kneussel M, Schindelin H. Elucidating the Molecular Basis for Inhibitory Neurotransmission Regulation by Artemisinins. Neuron. 2019 Feb 20;101(4):673-689.e11. doi: 10.1016/j.neuron.2019.01.001.
Hines RM, Maric HM, Hines DJ, Modgil A, Panzanelli P, Nakamura Y, Nathanson AJ, Cross A, Deeb T, Brandon NJ, Davies P, Fritschy JM, Schindelin H, Moss SJ. Developmental seizures and mortality result from reducing GABAA receptor α2-subunit interaction with collybistin. Nat Commun. 2018 Aug
7;9(1):3130. doi: 10.1038/s41467-018-05481-1.
Büchel G, Carstensen A, Mak KY, Roeschert I, Leen E, Sumara O, Hofstetter J, Herold S, Kalb J, Baluapuri A, Poon E, Kwok C, Chesler L, Maric HM, Rickman DS, Wolf E, Bayliss R, Walz S, Eilers M. Association with Aurora-A Controls N-MYC- Dependent Promoter Escape and Pause Release of RNA Polymerase II during the Cell Cycle. Cell Rep. 2017 Dec 19;21(12):3483-3497. doi: 10.1016/j.celrep.2017.11.090.
Maric HM*, Hausrat TJ, Neubert F, Dalby NO, Doose S, Sauer M, Kneussel M, Strømgaard K. Gephyrin-binding peptides visualize postsynaptic sites and modulate neurotransmission. Nat Chem Biol. 2017 Feb;13(2):153-160. doi: 10.1038/nchembio.2246.
(*First authorship and shared corresponding authorship)
Cheng J, Sahani S, Hausrat TJ, Yang JW, Ji H, Schmarowski N, Endle H, Liu X, Li Y, Böttche R, Radyushkin K, Maric HM, Hoerder-Suabedissen A, Molnár Z, Prouvot PH, Trimbuch T, Ninnemann O, Huai J, Fan W, Visentin B, Sabbadini R, Strømgaard K, Stroh A, Luhmann HJ, Kneussel M, Nitsch R, Vogt J. Precise Somatotopic Thalamocortical Axon Guidance Depends on LPA-Mediated PRG-2/Radixin Signaling. Neuron. 2016 Oct 5;92(1):126-142. doi: 10.1016/j.neuron.2016.08.035.
Maric HM*, Kasaragod VB*, Hausrat TJ, Kneussel M, Tretter V, Strømgaard K, Schindelin H. Molecular basis of the alternative recruitment of GABA(A) versus glycine receptors through gephyrin. Nat Commun. 2014 Dec 22;5:5767. doi: 10.1038/ncomms6767.
(* shared first authorship)
Maric HM, Kasaragod VB, Haugaard-Kedström L, Hausrat TJ, Kneussel M, Schindelin H, Strømgaard K. Design and synthesis of high-affinity dimeric inhibitors targeting the interactions between gephyrin and inhibitory neurotransmitter receptors. Angew Chem Int Ed Engl. 2015 Jan 7;54(2):490-4. doi: 10.1002/anie.201409043.
Selected as Hot Paper – Outstanding importance in a rapidly evolving field of high current interest
Maric HM, Kasaragod VB, Schindelin H. Modulation of gephyrin-glycine receptor affinity by multivalency. ACS Chem Biol. 2014 Nov 21;9(11):2554-62. doi: 10.1021/cb500303a.
Tretter V, Mukherjee J, Maric HM, Schindelin H, Sieghart W, Moss SJ. Gephyrin, the enigmatic organizer at GABAergic synapses. Front Cell Neurosci. 2012 May 15;6:23. doi: 0.3389/fncel.2012.00023.
Maric HM, Mukherjee J, Tretter V, Moss SJ, Schindelin H. Gephyrin-mediated γ-aminobutyric acid type A and glycine receptor clustering relies on a common binding site. J Biol Chem. 2011 Dec 9;286(49):42105-14. doi: 10.1074/jbc.M111.303412.
Mukherjee J, Kretschmannova K*, Gouzer G*, Maric HM*, Ramsden S, Tretter V, Harvey K, Davies PA, Triller A, Schindelin H, Moss SJ. The residence time of GABA(A)Rs at inhibitory synapses is determined by direct binding of the receptor α1 subunit to gephyrin. J Neurosci. 2011 Oct 12;31(41):14677-87. doi: 10.1523/JNEUROSCI.2001-11.2011.
(*shared second authorship)
Tretter V, Kerschner B, Milenkovic I, Ramsden SL, Ramerstorfer J, Saiepour L, Maric HM, Moss SJ, Schindelin H, Harvey RJ, Sieghart W, Harvey K. Molecular basis of the γ-aminobutyric acid A receptor α3 subunit interaction with the clustering protein gephyrin. J Biol Chem. 2011 Oct 28;286(43):37702-11. doi: 10.1074/jbc.M111.291336.
Vladimir has graduated magna cum laude from The Hebrew University of Jerusalem with B.Sc. in Pharmacy and M.Sc. in Medicinal Chemistry. Having a highly versatile background he fitted perfectly into our team and in June 2018 began working on microarray-based development of novel peptide probes and their integration in super resolution fluorescent microscopy. He currently focuses on the probes targeting Gephyrin – the universal hallmark and the major scaffolding protein of the inhibitory neuronal synapse.
Khayenko V, Maric HM. Targeting GABAAR-Associated Proteins: New Modulators, Labels and Concepts. Front Mol Neurosci. 2019;12:162. Published 2019 Jun 26. doi:10.3389/fnmol.2019.00162
Dr. Hans Maric
Clemens graduated from the University of Wuerzburg with an M.Sc. in Biochemistry in 2019, including a research stay at the Oregon Health and Science University in 2018. Since the start of his doctoral studies, he focuses on the profiling of native protein-protein interactions using complementary high-throughput technologies.
Ivan has graduated from the Università degli Studi "Gabriele d'Annunzio Chieti-Pescara" (Italy). Currently he focuses on the characterization of new auto antigens in the nodal and paranodal region by using a microarray approach and other technologies to characterize this kind of molecular interactions.
Junior Group Leader at the Rudolf Virchow Center of the University of Würzburg (since January 2018)
|04/2015-07/2017||Assistant Professor, Center for Biopharmaceuticals, University of Copenhagen, Denmark|
|07/2013-03/2015||Postdoctoral Fellow, Lundbeck Trust, Copenhagen, Denmark|
|12/2012-06/2013||Postdoctoral Fellow, Career Development Fellowship, GSLS Würzburg|
|2008 - 2012||Ph.D. Student, Rudolf Virchow Center, Würzburg, Germany|
|2002 - 2008||MSc (Diplom) in Chemistry, University of Würzburg, Germany |
Co-inventor of a novel biopharmaceutical substance PA 2015 70783 and PCT DK2016 050369 and co-author of 14 peer-reviewed publications with an accumulated impact of +123, so far yielding over 400 citations.
Fellowships, Awards and External Funding
Association with the CRC/Transregio 166 - Receptor Light (2019)
Material Costs Allowance of the Fonds of the chemical industry (FCI) (2018)
Excellent Ideas Program, Fellowship fo the University of Würzburg (2018 - 2022)
Fonds der chemischen Industrie „Exzellente Ideen“ Programm (2018)
Hoerslev Fonden (2018)
Torben og Alice Frimodts Fond (2017)
Brødrene Hartmanns Fond (2016)
Lundbeck Fellowship (2013 - 2015)
GSLS Career Development Fellowship (2012 - 2013)