51猎奇

Post-transcriptional regulation is a key stage of gene regulation and comprises the homeostasis of mRNA levels for a functional cell. Misbalance of these levels is a major cause for diseases like autoimmunity and cancer.

We are studying regulatory RNA-protein complexes that decide about the fate of mRNAs and thereby form a major regulatory parameter in cell development, during immune responses and in cancer progression. mRNAs contain untranslated regions (UTRs) in their 5鈥� and 3鈥� termini that are full of cis-regulatory elements which can either be structured moieties like stem-loops, extended double-stranded stretches of RNA or short linear sequences. It appears that mRNAs are regulated through the interplay of multiple of these cis elements, that are eventually organized in hubs. trans-acting factors are mainly microRNAs and RNA-binding proteins (RBPs) with their RNA-binding domains (RBDs) that recognize the cis elements and provoke downstream effects decisive for the fate of the mRNA. These can result in mRNA decay, protection, splicing, transport or its translational inhibition. Apparently the engagement of mRNA and proteins is a key checkpoint for the regulation of mRNA turnover and is not only affected by the expression levels of RBPs, but also by the spatiotemporal availability and organization of relevant RNA cis elements. Those might be masked in RNA secondary structure, by modifications or other RBPs.

Scheme of an mRNA with various cis-regulatory elements in its 3'-untranslated region (UTR). These are recognized by trans factors like RNA-binding proteins through cognate RNA-binding domains (RBDs).

Nature has evolved various concepts of RNA-protein interactions that we are only starting to understand in detail. RBPs normally find their targets either through a highly-specific and affine recognition of structured RNA cis elements (e.g. the by the Roquin ROQ domain) or the multivalent interaction of multiple RNA-binding domains (RBDs) with sequentially arranged short linear single-stranded cis elements (e.g. as known for IMP proteins). In either case, the prediction and identification of the exact target mRNAs is hampered by a likely higher-order organization of extended RNA regions involved in the interaction with the protein. The more, a certain degree of plasticity is achieved by complex-intrinsic dynamics and molecular flexibility.

Two concepts of mRNA 3'-UTR recognition by either a highly specific domain binding to structured RNA (left, exemplified by the Roquin ROQ domain bound to a stem-loop RNA element) or a multidomain RBP that encounters sequential short linear RNA elements (right, a tandem KH domain of IMP3 represents two of six potential RBDs), both to be found in disease-related mRNA regulation.

In order to dissect the networks of regulatory cis-trans interactions we determine atom-resolved pictures of mRNA 3'-UTR cis-regulatory elements in complex with RBPs using a broad set of methods from structural biology complemented by RNA- and protein-biochemical/biophysical methods. We are working in close collaboration with scientists from the fields of cell biology, immunology and big data for the mutual exchange of new finding and the transfer of identified structural determinants into living systems. We thereby hope to contribute to a broader understanding of mRNA-encoded gene regulation at the onset of diseases.

Our Integrated Structural Biology approach implements all kinds of methods to help obtaining molecular pictures and derive mechanistic concepts that are later on validated in functional assays with collaborating groups. In turn, we also exploit data that suggest novel target mRNAs and their cis elements to be regulated by our RBPs of interest.

Find all our publications .

Selected relevant publications from previous work:

Tants JN, Schlundt A. Advances, Applications, and Perspectives in Small-Angle X-Ray Scattering of RNA.

ChemBioChem. 2023 (in press). Coverstory!

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Korn SM, Dhamotharan K, Jeffries CM, Schlundt A. The preference signature of the SARS-CoV-2 Nucleocapsid NTD for its 5'-genomic RNA elements.

Nat. Commun. 2023 Jun 7.

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von Ehr J, Korn SM, Wei脽 L, Schlundt A. 1H, 13C, 15N backbone chemical shift assignments of the extended ARID domain in human AT-rich interactive domain protein 5a (Arid5a).

Biomol. NMR Assign. 2023 Jun;17.

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Schulte J, Tants JN, Von Ehr J, Schlundt A, Morgner N. Determination of dissociation constants via quantitative mass spectrometry.

Front Anal. Sci. 2023 Feb 24.

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Korn SM, Von Ehr J, Dhamotharan K, Tants JN, Abele R, Schlundt A. Insight into the Structural Basis for Dual Nucleic Acid-Recognition by the Scaffold Attachment Factor B2 Protein.

Int J Mol Sci. 2023 Feb 7.

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Duchardt-Ferner E, Ferner J, F眉rtig B, Hengesbach M, Richter C, Schlundt A, Sreeramulu S, Wacker A, Weigand JE, Wirmer-Bartoschek J, Schwalbe H. The COVID19-NMR Consortium: A Public Report on the Impact of this New Global Collaboration.

Angew Chem Int Ed Engl. Epub 2023 Feb 7.

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Berg H, Wirtz Martin MA, Altincekic N, Alshamleh I, Kaur Bains J, Blechar J, Ceylan B, de Jesus V, Dhamotharan K, Fuks C, Gande SL, Hargittay B, Hohmann KF, Hutchison MT, Marianne Korn S, Krishnathas R, Kutz F, Linhard V, Matzel T, Meiser N, Niesteruk A, Pyper DJ, Schulte L, Trucks S, Azzaoui K, Blommers MJJ, Gadiya Y, Karki R, Zaliani A, Gribbon P, da Silva Almeida M, Dinis Anobom C, Bula AL, B眉tikofer M, Putinhon Caruso 脥, Caterina Felli I, Da Poian AT, Cardoso de Amorim G, Fourkiotis NK, Gallo A, Ghosh D, Gomes-Neto F, Gorbatyuk O, Hao B, Kurauskas V, Lecoq L, Li Y, Cunha Mebus-Antunes N, Mompe谩n M, Cristtina Neves-Martins T, Ninot-Pedrosa M, Pinheiro AS, Pontoriero L, Pustovalova Y, Riek R, Robertson AJ, Jose Abi Saad M, Trevi帽o M脕, Tsika AC, Almeida FCL, Bax A, Henzler-Wildman K, Hoch JC, Jaudzems K, Laurents DV, Orts J, Pierattelli R, Spyroulias GA, Duchardt-Ferner E, Ferner J, F眉rtig B, Hengesbach M, L枚hr F, Qureshi N, Richter C, Saxena K, Schlundt A, Sreeramulu S, Wacker A, Weigand JE, Wirmer-Bartoschek J, W枚hnert J, Schwalbe H. Comprehensive Fragment Screening of the SARS-CoV-2 Proteome Explores Novel Chemical Space for Drug Development.

Angew Chem Int Ed Engl. 2022 Nov 14.

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Pontoriero L, Schiavina M, Korn SM, Schlundt A*, Pierattelli R*, Felli IC*. NMR Reveals Specific Tracts within the Intrinsically Disordered Regions of the SARS-CoV-2 Nucleocapsid Protein Involved in RNA Encountering.

Biomolecules. 2022 Jul 2.

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Mertinkus KR, Gr眉n JT, Altincekic N, Bains JK, Ceylan B, Ferner JP, Frydman L, F眉rtig B, Hengesbach M, Hohmann KF, Hymon D, Kim J, Knezic B, Novakovic M, Oxenfarth A, Peter SA, Qureshi NS, Richter C, Scherf T, Schlundt A, Schnieders R, Schwalbe H, Stirnal E, Sudakov A, V枚gele J, Wacker A, Weigand JE, Wirmer-Bartoschek J, Martin MAW, W枚hnert J. 1H, 13C and 15N chemical shift assignment of the stem-loops 5b鈥�+鈥塩 from the 5'-UTR of SARS-CoV-2.

Biomol. NMR Assign. 2022 Apr 16.

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Tants JN, Becker LM, McNicoll F, M眉ller-McNicoll M, Schlundt A. NMR-derived secondary structure of the full-length Ox40 mRNA 3'UTR and its multivalent binding to the immunoregulatory RBP Roquin.

Nucleic Acids Res. 2022 Apr 22.

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Korn SM, Schlundt A. Structures and nucleic acid-binding preferences of the eukaryotic ARID domain. Review.

Biol Chem. 2022 Feb 7.

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Schamber T, Binas O, Schlundt A, Wacker A, Schwalbe H. Characterization of Structure and Dynamics of the Guanidine-II Riboswitch from Escherichia coli by NMR Spectroscopy and Small-Angle X-ray Scattering (SAXS).

Chembiochem. 2022 Feb 4

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Sreeramulu S, Richter C, Berg H, Wirtz Martin MA, Ceylan B, Matzel T, Adam J, Altincekic N, Azzaoui K, Bains JK, Blommers MJJ, Ferner J, F眉rtig B, G枚bel M, Gr眉n JT, Hengesbach M, Hohmann KF, Hymon D, Knezic B, Martins JN, Mertinkus KR, Niesteruk A, Peter SA, Pyper DJ, Qureshi NS, Scheffer U, Schlundt A, Schnieders R, Stirnal E, Sudakov A, Tr枚ster A, V枚gele J, Wacker A, Weigand JE, Wirmer-Bartoschek J, W枚hnert J, Schwalbe H. Exploring the Druggability of Conserved RNA Regulatory Elements in the SARS-CoV-2 Genome.

Angew Chem Int Ed Engl. 2021Aug 23 (online).

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Korn SM, Ulsh枚fer C, Schneider T, Schlundt A. Structures and target RNA preferences of the multi-domain RNA-binding protein family of IGF2BPs: An overview. Review.

Structure. 2021May 21 (online).

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Altincekic N, Korn SM, Qureshi NS, Dujardin M, Ninot-Pedrosa M, 鈥�, B枚ckmann A*, 鈥�, Schwalbe H*, 鈥�,  Hengesbach M*, Schlundt A*. Large-scale recombinant production of the SARS-CoV-2 proteome for high-throughput and structural biology applications.

Front Mol. Biosci. 2021 May 10 (online).

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Wang Y, Kirkpatrick J, Zur Lage S, Korn SM, Nei脽ner K, Schwalbe H, Schlundt A, Carlomagno T. 1H, 13C, and 15N backbone chemical-shift assignments of SARS-CoV-2 non-structural protein 1 (leader protein).

Biomol NMR Assign. 2021 Mar 26:1-9.

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F Dud谩s E, Puglisi R, Korn SM, Alfano C, Bellone ML, Piaz FD, Kelly G, Monaca E, Schlundt A, Schwalbe H, Pastore A. Backbone chemical shift spectral assignments of SARS coronavirus-2 non-structural protein nsp9.

Biomol NMR Assign. 2021 Mar 23:1-7.

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Korn SM, Lambertz R, F眉rtig B, Hengesbach M, L枚hr F, Richter C, Schwalbe H, Weigand JE, W枚hnert J, Schlundt A. 1H, 13C, and 15N backbone chemical shift assignments of the C-terminal dimerization domain of SARS-CoV-2 nucleocapsid protein.

Biomol NMR Assign. 2021 Apr;15(1):129-135.

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Korn SM, Dhamotharan K, F眉rtig B, Hengesbach M, L枚hr F, Qureshi NS, Richter C, Saxena K, Schwalbe H, Tants JN, Weigand JE, W枚hnert J, Schlundt A. 1H, 13C, and 15N backbone chemical shift assignments of the nucleic acid-binding domain of SARS-CoV-2 non-structural protein 3e.

Biomol NMR Assign. 2020 Oct;14(2):329-333.

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Wacker A, Weigand JE, Akabayov SR, Altincekic N, Bains JK, Banijamali E, Binas O, Castillo-Martinez J, Cetiner E, Ceylan B, Chiu LY, Davila-Calderon J, Dhamotharan K, Duchardt-Ferner E, Ferner J, Frydman L, F眉rtig B, Gallego J, Gr眉n JT, Hacker C, Haddad C, H盲hnke M, Hengesbach M, Hiller F, Hohmann KF, Hymon D, de Jesus V, Jonker H, Keller H, Knezic B, Landgraf T, L枚hr F, Luo L, Mertinkus KR, Muhs C, Novakovic M, Oxenfarth A, Palomino-Sch盲tzlein M, Petzold K, Peter SA, Pyper DJ, Qureshi NS, Riad M, Richter C, Saxena K, Schamber T, Scherf T, Schlagnitweit J, Schlundt A, Schnieders R, Schwalbe H, Simba-Lahuasi A, Sreeramulu S, Stirnal E, Sudakov A, Tants JN, Tolbert BS, V枚gele J, Wei脽 L, Wirmer-Bartoschek J, Wirtz Martin MA, W枚hnert J, Zetzsche H. Secondary structure determination of conserved SARS-CoV-2 RNA elements by NMR spectroscopy.

Nucl. Acid. Res. 2020 Dec 16;48(22):12415-12435.

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Binas O, Tants JN, Peter S, Janowski R, Davydova E, Braun J, Niessing D,Schwalbe H, Weigand J*, Schlundt A*. Structural basis for the recognition of transiently structured AU-rich elements by Roquin.

Nucl. Acid. Res. 2020 Jul 27;48(13):7385-7403

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LingarajuM, Johnsen D, Schlundt A, Langer LM, Basquin J, Sattler M, Heick Jensen T, Falk S, Conti E. The MTR4 helicase recruits nuclear adaptors of the human RNA exosome using distinct arch-interacting motifs.

Nat. Commun. 2019 Jul 29;10(1):3393.

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Schneider T, Hung LH, Aziz M, Wilmen A, Thaum S, Wagner J, Janowski R, M眉ller S, H眉ttelmaier S, Niessing D, Sattler M, Schlundt A*, BindereifA*. Combinatorial recognition of clustered RNA elements by the multidomain RNA-binding protein IMP3.

Nat. Commun. 2019 May 22;10(1):2266.

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Essig K, Kronbeck N, Guimaraes JC, Lohs C, Schlundt A, Hoffmann A, Behrens G, Brenner S, Kowalska J, Lopez-Rodriguez C, Jemielity J, Holtmann H, Reiche K, Hackerm眉ller J, Sattler M, Zavolan M, Heissmeyer V. Roquin targets mRNAs in a 3鈥�-UTR-specific manner by different modes of regulation.

Nat. Commun. 2018 Sep 19;9(1):3810.

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Schlundt A, Buchner S, Janowski R, Heydenreich T, Heermann R, Lassak J, Geerlof A, Stehle R, Niessing D, Jung K, Sattler M. Structure-function analysis of the DNA-binding domain of a transmembrane transcriptional activator.

Sci. Rep. 2017 Apr 21; 1051.

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Schlundt A, Tants J, Sattler M. Integrated structural biology to unravel mechanisms of RNA-protein recognition. Review

Methods. 2017 Mar 16. pii: S1046-2023(17)30120-2.

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Edelmann FT, Schlundt A, Heym RG, Jenner A, Niedner A, Syed MI, Paillart J, Stehle R, Janowski R, Sattler M, Jansen R, Niessing D. Molecular architecture and dynamics of RNA recognition by an mRNA-transport complex.

Nat. Struct. Mol. Biol. 2017 Feb;24(2):152-161.

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Schlundt A*, Niessing D, Heissmeyer V, Sattler M*. RNA recognition by Roquin in posttranscriptional gene regulation. Review.

Wiley Interdiscipl. Rev. RNA. 2016 Jul;7(4):455-69.

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Janowski R*, Heinz GA*, Schlundt A*, Wommelsdorf N, Brenner S, Gruber AR, Blank M, Buch T, Buhmann R, Zavolan M, Niessing D, Heissmeyer V, Sattler M. Roquin recognizes a non-canonical hexaloop structure in the 3'-UTR of Ox40.

Nat. Commun. 2016 Mar 24;7:11032.

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Buchner S, Schlundt A, Lassak J, Sattler M, Jung K. Structural and Functional Analysis of the Signal-Transducing Linker in the pH-Responsive One-Component System CadC of Escherichia coli.

J. Mol. Biol. 2015 Jul 31;427(15):2548-61.

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SchlundtA*, Heinz GA*, Janowski R*, Geerlof A, Stehle R, Heissmeyer V, Niessing D, Sattler M. Structural basis for RNA recognition in roquin-mediated post-transcriptional gene regulation.

Nat.Struct. Mol. Biol. 2014 Aug;21(8):671-8.

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*equal contribution or corresponding authorship