Speaker: Reinhard Lührmann, PhD
Study of chemistry at the University of Münster, diploma (1973),
PhD with Prof. Gassen at the University of Münster (1973-1975), postdoctoral fellow with Prof. H.G. Wittmann at the Max Planck Institute for Molecular Genetics, Berlin (1976-1980),
head of a Max Planck junior research group, Max Planck Institute for Molecular Genetics (1981-1988),
German Habilitation in biochemistry and molecular biology at the Free University of Berlin (1982),
Professor for Physiological Chemistry and Molecular Biology at the University of Marburg (1988-1999),
Director and Scientific Member at the Max Planck Institute for Biophysical Chemistry, Honorary Professor at the University of Marburg (since 2000).
Work Email: email@example.com
Time: 10:00-12:00 am , Nov. 08 (Wednesday)
Venue: Lecture Hall, SIBS Main Building, Yueyang Road 320
Host: Prof. Zefeng Wang
CAS-MPG Partner Institute for Computational Biology
Title: Structural basis of pre-mRNA splicing
The spliceosome catalyses the removal of the intron from nuclear pre-mRNAs and assembles initially into a pre-catalytic ensemble, termed complex B, which contains the snRNPs U1, U2 and the U4/U6.U5 tri-snRNP and numerous non-snRNP proteins. For catalytic activation the spliceosome undergoes a major structural rearrangement, mediated by the Brr2 RNA helicase, yielding the activated spliceosome (Bact complex). The final catalytic activation of the spliceosome requires an additional restructuring step by the RNA helicase Prp2, generating the B* complex which catalyses the first step of the splicing reaction, yielding the C complex. Subsequently the catalytic center of the spliceosome has to be remodeled by the RNA helicase Prp16 to generate the C* complex as a pre-requisite for second step catalysis.
Using cryo electron microscopy we have investigated the 3D structure of the human U4/U6.U5 tri-snRNP complex and several purified spliceosomal complexes. Our tri-snRNP model reveals how the spatial organization of Brr2 RNA helicase prevents premature U4/U6 RNA unwinding in isolated human tri-snRNPs and how the Sad1 protein likely tethers Brr2 to its pre-activation position. A medium-resolution structure of the human B complex reveals that Brr2 undergoes a large-scale movement during stable B complex formation where it is juxtaposed close to the U4 RNP domain. The Cryo-EM structure of the purified S. cerevisiae Bact complex reveals how the first step reactants (i.e. the 5'splice site and the branch site adenosine) are sequestered by protein prior to catalysis and provide insights into the molecular remodeling events that must be facilitated by Prp2 in order to generate a catalytically active B* spliceosome. Finally, I will also present the Cryo-EM 3D structure of a human C* complex, which has undergone the Prp16-mediated remodeling step.
Our combined studies show that the spliceosome is an extremely dynamic molecular machine which undergoes dramatic large-scale structural changes during one round of pre-mRNA splicing.
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