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Swiss Society for Crystallography - Howard Flack Crystallographic Lectures Series

Online Archiv

11. October 2021

Online via Zoom

Invited Talk

Catalytic cycling of human mitochondrial Lon protease homolog


Speaker: Prof. Jan Pieter Abrahams, University of Basel

Host: Prof. Dr. Antonia Neels, Head of the Center for X-ray Analytics, Empa



The mitochondrial Lon protease homolog (LonP1) hexamer regulates mitochondrial health by digesting proteins from the mitochondrial matrix that are damaged or must be removed. Here, we describe nine different, nucleotide dependent conformational states that we determined by cryo-EM. We show that LonP1 has an additional, previously unidentified Thr-type proteolytic center. Although resolutions locally extended to 3.6 Å for the best ordered states, the Nterminal domains were poorly ordered in all conformations. These N-domains formed an assembly with threefold symmetry and the orientation of its threefold axis depended on the conformational state. For most states we could infer the nucleotide occupancy. Our data indicate how LonP1 recognizes, binds, translocates and digests substrate protein. We propose that translocation requires a sixfold rotational binding change mechanism with threefold rocking motions of the N-domain assembly. The rocking motions of the N-domain assembly, together with its flexibility, may assist thermal unfolding of the substrate protein. Our data suggest that ATP hydrolysis prevents translocation reversal, and we propose LonP1 functions as a Brownian ratchet.


About the Speaker 





Jan Pieter Abrahams is a structural biologist, currently at Basel University (prof.) and the Paul Scherrer Institute (head of LBR). He loves seeing important molecular structures of life that nobody has seen before, in ways that nobody has tried before. For this purpose, he has developed novel methods in high-resolution bioimaging, which include computation, chemistry, and physics. After his PhD in Leiden, he moved to the LMB in Cambridge, where, working in the groups of Andrew Leslie and John Walker, he solved the structure of the F1-ATPase (resulting in the Nobel Prize in Chemistry for John Walker). He could only solve this structure with the novel approaches in X-ray data collection and crystallographic phasing that he developed specifically for this purpose and that have now become part of mainstream crystallography. In 1997, he returned to Leiden to become a full professor, where he studied serpins, viruses, ribosomal complexes, DNA repair proteins, microtubule complexes, enzymes, and amyloid-formation using X-ray crystallography, EM, NMR, AFM and spectroscopic techniques. Between 1997 and 2021, as a PI, he raised more than 36 MEuro in competitive funding for this and other work; many of these funds were for joint research projects and joint infrastructure. In this period, four companies were spun out of his research group. In 2015, he moved to Switzerland as professor at the Basel Biozentrum and head of the Laboratory of Biomolecular Research of the Paul Scherrer Institute, where he established protein electron nanocrystallography. Here he also studied the human mitochondrial Lon protease homolog (LonP1), identifying nine different active conformations that together explained how LonP1 recognizes, unfolds, translocates and proteolyzes substrate proteins that are damaged or need to be removed.