Maric Group
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.
Technology
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.
Khayenko V, Schulte C, Reis SL, Avraham O, Schietroma C, Worschech R, Nordblom NF, Kachler S, Villmann C, Heinze KG, Schlosser A, Schueler-Furman O, Tovote P, Specht CG, Maric HM. A Versatile Synthetic Affinity Probe Reveals Inhibitory Synapse Ultrastructure and Brain Connectivity. Angew Chem Int Ed Engl. 2022 Jul 25;61(30):e202202078. doi: 10.1002/anie.202202078. Epub 2022 May 6.
Schulte C, Soldà A, Spänig S, Adams N, Bekić I, Streicher W, Heider D, Strasser R, Maric HM. Multivalent binding kinetics resolved by fluorescence proximity sensing. Commun Biol. 2022 Oct 7;5(1):1070. doi: 10.1038/s42003-022-03997-3.
Talucci I, Maric HM. Peptide Microarrays for Studying Autoantibodies in Neurological Disease. Methods Mol Biol. 2023;2578:17-25. doi: 10.1007/978-1-0716-2732-7_2.
Schulte C, Khayenko V, Maric HM. Peptide Microarray-Based Protein Interaction Studies Across Affinity Ranges: Enzyme Stalling, Cross-Linking, Depletion, and Neutralization. Methods Mol Biol. 2023;2578:143-159. doi: 10.1007/978-1-0716-2732-7_10.
Dos Reis R, Kornobis E, Pereira A, Tores F, Carrasco J, Gautier C, Jahannault-Talignani C, Nitschké P, Muchardt C, Schlosser A, Maric HM, Ango F, Allemand E. Complex regulation of Gephyrin splicing is a determinant of inhibitory postsynaptic diversity. Nat Commun. 2022 Jun 18; 13: 3507. doi: 10.1038/s41467-022-31264-w
Khayenko V, Schulte C, Reis SL, Avraham O, Schietroma C, Worschech R, Nordblom NF, Kachler S, Villmann C, Heinze KG, Schlosser A, Schueler-Furman O, Tovote P, Specht CG, Maric HM. A Versatile Synthetic Affinity Probe Reveals Inhibitory Synapse Ultrastructure and Brain Connectivity. Angew Chem Int Ed Engl. 2022 Apr 14:e202202078. doi: 10.1002/anie.202202078
Schulte C, Khayenko V, Gupta AJ, Maric HM. Low-cost synthesis of peptide libraries and their use for binding studies via temperature-related intensity change. STAR Protoc. 2021 Jun 15;2(3):100605. doi: 10.1016/j.xpro.2021.100605.
Khayenko V, Maric HM. Innovative affinitätsbasierte Markierungen für die High-End-Mikroskopie. BIOspektrum. 2021 Jul 27, 709-712. doi: 10.1007/s12268-021-1672-7.
Makbul C, Khayenko V, Maric HM, Böttcher B. Conformational Plasticity of Hepatitis B Core Protein Spikes Promotes Peptide Binding Independent of the Secretion Phenotype. Microorganisms. 2021 Apr 29;9(5):956. doi: 10.3390/microorganisms9050956.
Schulte C and Maric HM. Expanding GABAAR pharmacology via receptor-associated proteins. Curr Opin Pharmacol, 56 (2021). 57:98-106. doi:10.1016/j.coph.2021.01.004.
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.
Giorgia Danti
Josef-Schneider-Str. 2
Christiane Huhn
Josef-Schneider-Str. 2
Sonja Kachler
Josef-Schneider-Str. 2
Vladimir Khayenko
Josef-Schneider-Str. 2
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.
Publications:
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
Josef-Schneider-Str.2
Clemens Schulte
Josef-Schneider-Str. 2
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 Talucci
Josef-Schneider-Str. 2
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.
Omkar Valanju
Josef-Schneider-Str. 2
Current position
Junior Group Leader at the Rudolf Virchow Center of the University of Würzburg (since January 2018)
Research Experience
| 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 |
Career
| 2002-2008 | Chemistry (Diplom), JMU Würzburg sehr gut |
| 2012 | Phd, JMU Würzburg, summa cum laude |
| 2013 | Postdoc, JMU Würzburg |
| 2013-2015 | Postdoc, University of Copenhagen, Denmark |
| 2015 | Postdoc, Center for Molecular Neurogenetics, University Hospital Hamburg Eppendorf |
| 2015-2017 | Assistant Professor, Center for Biopharmaceuticals, Denmark |
| 2018-2021 | Junior Group Leader, JMU Würzburg |
| since 2021- | Emmy Noether Group Leader, Rudolf Virchow Center |
Patents
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.
Awards and Funding
| 2012 | GSLS Career Development Fellowship |
| 2013 | Lundbeck Foundation Fellowship, Denmark |
| 2015 | Torben og Alice Frimodts Fond, Denmark |
| 2016 | Brødrene Hartmanns Fonds, Denmark |
| 2017 | Hørslev-Fonden, Denmark |
| 2018 | Fonds der chemischen Industrie e.V. |
| 2019 | TRR/SFB 166 Receptor Light |
| 2020 | Anschubförderung, JMU Würzburg |
| since 2018 | Exzellente Ideen Förderung, JMU Würzburg |
| since 2021 | Förderung durch das Interdisziplinäre Zentrum für klinische Forschung Würzburg |
| since 2021 | Emmy Noether Förderung der DFG |
