Lührmann, Reinhard, Prof. Dr.
Professor, Director at the Max Planck Institute for Biophysical Chemistry
- Dr. rer. nat (Ph. D.), University of Münster (1975)
- Research group leader, Max Planck Institute for Molecular Genetics, Berlin (1981 - 1988)
- Professor of Biochemistry and Molecular Biology at the University of Marburg (1988 - 1999)
- Director, Dept. of Cellular Biochemistry, Max Planck Institute for Biophysical Chemistry, Göttingen (since 1999)
- since 2007: Honorary Professor at the Philipps University of Marburg (since 2000) and Georg August University of Göttingen
Major Research Interests
Most metazoan pre-mRNAs contain multiple introns and exons. In order to generate mature mRNA, the introns must be excised from the pre-mRNA, a process termed pre-mRNA splicing. In many cases, alternative splicing generates different mRNAs from a single pre-mRNA by the regulated removal of different sections of the RNA, a process which greatly expands the complexity of the repertoire of proteins that can be expressed from relatively small genomes. Splicing is catalysed by a large macromolecular machine, termed the spliceosome which consists of the small nuclear RNAs (U1, U2, U4, U5 and U6) and more than 150 proteins, 50 of which are associated with the snRNAs to form snRNPs.
In our laboratory, intense efforts are focussed on understanding how the spliceosome recognizes and binds the intron ends and discriminates them from exons. This is an especially confounding problem in metazoans because, in contrast to lower eucaryotes such as yeast, pre-mRNA introns are often extremely long (104-105 nucleotides), while exons are generally small (less than 300 nucleotides). Another major goal of our research is the elucidation of the mechanisms by which the spliceosome assembles into a catalytically active machine and catalyses intron excision. None of the building blocks of the spliceosome contains an active site. Instead, the catalytically active domain must be assembled anew on to each intron, a highly dynamic process which entails dramatic structural rearrangements of the RNP structure of the spliceosome, and which is orchestrated by the successive action of more than 10 enzymes such as RNA helicases and GTPases, as well as by posttranslational phosphorylation of a multitude of spliceosomal proteins. Our studies involve a large number of experimental approaches, including biochemical purification of entire spliceosomes or large protein ensembles, and characterization of their proteins by mass spectrometry; RNA biology methods such as enzymatic engineering of RNA molecules, RNA structure probing and RNA interference methods; production of recombinant proteins and antibodies; procedures for the investigation of protein-protein and protein-RNA interactions in vitro and in vivo; and biophysical methods such as fluorescence spectroscopy.
Finally, we are investigating the 3D structure of purified spliceosomes or major building blocks thereof using electron microscopic approaches and X ray crystallography. Our studies on the regulatory mechanisms of constitutive and alternative pre-mRNA splicing involve mainly mammalian systems. As the basic mechanisms of splicing catalysis appear to be evolutionarily highly conserved, we are also taking advantage of molecular genetic approaches in bakers yeast to elucidate the structure and function of the catalytic core domain of the spliceosome.
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