The Fas protein can either inhibit or promote the controlled cell death (apoptosis), depending on the isoform in which it occurs. Together with international colleagues, researchers from the Helmholtz Zentrum M\u00fcnchen and the Technical University of Munich have elucidated how this decision is guided. These results provide new insights into the molecular mechanisms of tumor diseases and have now been published in eLife<\/i>. Please find a video of the PI explaining the story here: https:\/\/vimeo.com\/193368352<\/a><\/p>\n
We know the problem: When assembling the parts and pieces of furniture purchased at a store, everyone uses the same blueprint. Nevertheless, the end product can differ greatly in the course of assembling the whole product over several intermediate steps. Something quite similar can happen during the production of proteins from genes. The genome (the blueprint) is first transcribed into a messenger molecule, the mRNA, and then translated into proteins (furniture). However, the mRNA can be altered and trimmed during intermediate steps in a process called alternative splicing, so that ultimately different proteins are produced from the same blueprint.<\/p>\n
An interesting example of alternative splicing is the mRNA of the Fas gene*. Depending on which intermediate steps take place, the finished protein can either prevent or promote controlled cell death (apoptosis). “The right balance between these opposing results is dependent on the cell type and can also lead to uncontrolled cell growth and cancer when alternative splicing is dysregulated,” explains Professor Michael Sattler, Director of the Institute of Structural Biology (STB) at Helmholtz Zentrum M\u00fcnchen. In collaboration with Professor Juan Valc\u00e1rcel Ju\u00e1rez of the Centre de Regulaci\u00f3 Gen\u00f2mica (CRG) in Barcelona, he and his team have now gained insight into which intermediate steps are taken and how these lead to different isoforms of the Fas protein. <\/p>\n
“The focus of our interest was the protein RBM5, which often exhibits mutations in lung tumors,” says Dr. Andr\u00e9 Mour\u00e3o of the STB. “RBM5 helps to bring the spliceosome to the mRNA by binding to a spliceosomal protein”, explains coauthor Dr. Sophie Bonnal of the CRG Barcelona. In this central position, RBM5 decides which isoform of Fas is expressed and thus controls the balance between the two different isoforms.**<\/p>\n
“By employing nuclear magnetic resonance (NMR) spectroscopy at the Bavarian NMR Center in Garching, we were able to elucidate the spatial structure of RBM5-OCRE in complex with SmN (a protein present in the spliceosome) and to understand exactly how these interaction occurs,” states Sattler, who directed the study.*** To confirm their findings, the scientists mutated the corresponding interaction residues of the proteins and observed that the interactions no longer took place in the test tube and that the splicing activities of RBM5 in cell culture was impaired. <\/p>\n
“The process of alternative splicing affects numerous essential functions and processes in an organism, and dysregulation can trigger cancer. That is why it is very important to precisely understand the mechanisms that regulate these processes,” explains Sattler, summarizing the results. According to the authors, only a few protein interactions that influence alternative splicing by binding to spliceosomal proteins have been analyzed in such structural depth. In the future, the researchers want to determine exactly how RBM5 binds to the mRNA and whether there are additional interactions with the spliceosome, which consists of numerous other components. <\/p>\n
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Further Information<\/p>\n
* Fas is also known as CD95 or APO-1. Depending on whether a specific region (exon 6) is contained in the mRNA or not, a membrane-bound pro-apoptotic protein or a soluble isoform arises in the cell interior, which counteracts apoptosis. As a pro-apoptotic protein, Fas prevents errant cells from multiplying uncontrolled, whereas the anti-apoptotic isoform leads to the proliferation of such cells.<\/p>\n
** The name is an acronym for RNA Binding Motif 5. RBM5 is a protein, which is demonstrably dysregulated in different cancers (especially in the lungs). <\/p>\n
*** A so-called OCRE (octamer repeat of aromatic residues) domain of the protein RBM5 binds to the C-terminus of the spliceosomal protein SmN and is thus important for the regulation of the alternative splicing. <\/p>\n
Background:
\nIn addition to his work at Helmholtz Zentrum M\u00fcnchen, Prof. Dr. Sattler holds the chair of Biomolecular NMR Spectroscopy at Technische Universit\u00e4t M\u00fcnchen. He heads the Bavarian NMR Center, which is jointly operated by TUM and HMGU (http:\/\/www.bnmrz.org<\/a>). The Instituci\u00f3 Catalana de Recerca i Estudis Avan\u00e7ats (ICREA) in Barcelona in Spain (http:\/\/www.crg.eu\/en\/juan_valcarcel<\/a>) and the Institut de G\u00e9n\u00e9tique Mol\u00e9culaire de Montpellier in France also participated in the study.<\/p>\n
Publication:
\nMour\u00e3o, A. Bonnal, S. Soni, K. Warner, L. et al. (2016): Structural basis for the recognition of spliceosomal SmN\/B\/B’ proteins by the RBM5 OCRE domain in splicing regulation. eLife<\/i>, doi: 10.7554\/eLife.14707
\nhttps:\/\/elifesciences.org\/content\/5\/e14707<\/a> <\/p>\n
The Helmholtz Zentrum M\u00fcnchen, the German Research Center for Environmental Health, pursues the goal of developing personalized medical approaches for the prevention and therapy of major common diseases such as diabetes and lung diseases. To achieve this, it investigates the interaction of genetics, environmental factors and lifestyle. The Helmholtz Zentrum M\u00fcnchen is headquartered in Neuherberg in the north of Munich and has about 2,300 staff members. It 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. http:\/\/www.helmholtz-muenchen.de\/en<\/a><\/p>\n
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. http:\/\/www.helmholtz-muenchen.de\/stb<\/a><\/p>\n
Technical University of Munich (TUM) is one of Europe’s leading research universities, with more than 500 professors, around 10,000 academic and non-academic staff, and 40,000 students. Its focus areas are the engineering sciences, natural sciences, life sciences and medicine, combined with economic and social sciences. TUM acts as an entrepreneurial university that promotes talents and creates value for society. In that it profits from having strong partners in science and industry. It is represented worldwide with a campus in Singapore as well as offices in Beijing, Brussels, Cairo, Mumbai, San Francisco, and S\u00e3o Paulo. Nobel Prize winners and inventors such as Rudolf Diesel, Carl von Linde, and Rudolf M\u00f6\u00dfbauer have done research at TUM. In 2006 and 2012 it won recognition as a German “Excellence University.” In international rankings, TUM regularly places among the best universities in Germany. http:\/\/www.tum.de\/en\/homepage<\/a><\/p>\n
Contact for the media:
\nDepartment of Communication, Helmholtz Zentrum M\u00fcnchen – German Research Center for Environmental Health, Ingolst\u00e4dter Landstr. 1, 85764 Neuherberg – Tel. +49 89 3187 2238 – Fax: +49 89 3187 3324 – E-mail: presse@helmholtz-muenchen.de<\/a> <\/p>\n
Scientific Contact at Helmholtz Zentrum M\u00fcnchen:
\nProf. Dr. Michael Sattler, Helmholtz Zentrum M\u00fcnchen – German Research Center for Environmental Health, Institute for Structural Biology, Ingolst\u00e4dter Landstra\u00dfe 1, 85764 Neuherberg, Tel. +49 89 3187 3800, E-mail: sattler@helmholtz-muenchen.de<\/a>\n<\/p><\/p>\n","protected":false},"excerpt":{"rendered":"
The Fas protein can either inhibit or promote the controlled cell death (apoptosis), depending on the isoform in which it occurs. Together with international colleagues, researchers from the Helmholtz Zentrum M\u00fcnchen and the Technical University of Munich have elucidated how this decision is guided. These results provide new insights into the molecular mechanisms of tumor Read More<\/a><\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[],"tags":[],"class_list":["post-134385","post","type-post","status-publish","format-standard","hentry"],"_links":{"self":[{"href":"http:\/\/healthmedicinet.com\/i\/wp-json\/wp\/v2\/posts\/134385","targetHints":{"allow":["GET"]}}],"collection":[{"href":"http:\/\/healthmedicinet.com\/i\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"http:\/\/healthmedicinet.com\/i\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"http:\/\/healthmedicinet.com\/i\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"http:\/\/healthmedicinet.com\/i\/wp-json\/wp\/v2\/comments?post=134385"}],"version-history":[{"count":0,"href":"http:\/\/healthmedicinet.com\/i\/wp-json\/wp\/v2\/posts\/134385\/revisions"}],"wp:attachment":[{"href":"http:\/\/healthmedicinet.com\/i\/wp-json\/wp\/v2\/media?parent=134385"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"http:\/\/healthmedicinet.com\/i\/wp-json\/wp\/v2\/categories?post=134385"},{"taxonomy":"post_tag","embeddable":true,"href":"http:\/\/healthmedicinet.com\/i\/wp-json\/wp\/v2\/tags?post=134385"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}