Press Release

Structural Biology
24.03.2016

Roquin Recognizes Newly Identified RNA Motif in Genes

Scientists of Helmholtz Zentrum München have identified a previously unknown hairpin structure in the messenger RNA (mRNA) of immunologically relevant genes, which is recognized by the RNA-binding protein Roquin with a similar high affinity as the previously known decay element CDE (constitutive decay element). Both hairpin structures are physiologically important because they cooperate in Roquin-induced mRNA decay.

Ausschnitt aus der Kristallstruktur der Roquin ROQ-Domäne (grau, im Hintergrund angedeutet) im Komplex mit der neu identifizierten Hexa-loop RNA-Haarnadel / Quelle: HMGU

Roquin plays a key role in the activation and differentiation of T-cells. Through its regulatory intervention in the expression of proteins, Roquin is of critical importance to the immune tolerance of the body. "The elucidation of the target mRNA and its recognition is the basis for understanding Roquin function. This will enable future pharmacological modulations", said Professor Michael Sattler, director of the Institute of Structural Biology (STB) at Helmholtz Zentrum München.

Structure and function of novel regulatory motifs in messenger RNA

While transcription in the cell nucleus is based on the recognition of sequences in the DNA, post-transcriptional gene regulation in the cytoplasm by RNA-binding proteins is achieved through the combined binding of secondary structures and sequence of the RNA. This results in dynamic and highly complex regulatory mechanisms that play a key role in the establishment of physiological and pathological immune responses.

Elucidating these molecular processes provides the basis for a better understanding of these pathological immune responses. “The identification of different sequence motifs in mRNAs, which are bound by Roquin, now enables us to study how these various structures work together in larger cis-regulatory sequences of Roquin-controlled RNA molecules”, said Prof. Dr. Vigo Heissmeyer, head of the Research Unit Molecular Immunoregulation (AMIR) at Helmholtz Zentrum München.

Surprisingly, the studies show that not only a previously known RNA hairpin motif with three unpaired bases, but also a novel motif consisting of a loop with six unpaired bases is recognized by Roquin. “Characterizing the structure of the underlying protein complexes is here an important approach to the detailed understanding of the molecular bases of immunological processes. This can open up new avenues for targeted therapy of immune diseases in the future,” added Prof. Dr. Dierk Niessing, head of the research group RNA Biology and the X-ray crystallography platform (https://www.helmholtz-muenchen.de/en/stb/xray) at the Institute of Structural Biology.

Further Information

Original publication:
Janowski, R. et al. (2016). Roquin recognizes a non-canonical hexaloop structure in the 3'-UTR of Ox40, nature communications; DOI: 10.1038/ncomms11032
Link to journal publication

As German Research Center for Environmental Health, Helmholtz Zentrum München pursues the goal of developing personalized medical approaches for the prevention and therapy of major common diseases such as diabetes mellitus and lung diseases. To achieve this, it investigates the interaction of genetics, environmental factors and lifestyle. The Helmholtz Zentrum München has about 2,300 staff members and is headquartered in Neuherberg in the north of Munich. Helmholtz Zentrum München is a member of the Helmholtz Association, a community of 18 scientific-technical and medical-biological research centers with a total of about 37,000 staff members.

The Institute for Structural Biology (STB)  investigates the spatial structures of biological macromolecules, their molecular interactions and dynamics using integrated structural biology by combining X-ray crystallography, NMR-spectroscopy and other methods. Researchers at STB also develop NMR spectroscopy methods for these studies. The goal is to unravel the structural and molecular mechanisms underlying biological function and their impairment in disease. The structural information is used for the rational design and development of small molecular inhibitors in combination with chemical biology approaches.

The Research Unit Molecular Immunoregulation (AMIR) investigates the molecular mechanisms of physiological and pathological immune responses such as the autoimmune diseases type 1 diabetes and lupus erythematosus. The goal of AMIR is to understand the molecular programs in T cells, which enable the distinction between self and foreign antigenic structures. The focus is on post-transcriptional gene regulation.