Leonid A. Sazanov wird für seine wissenschaftlichen Leistungen auf dem Gebiet der Strukturbiologie von Membranproteinkomplexen ausgezeichnet.
Life of higher organisms, including humans, is made possible by the production of energy (as ATP molecules) in mitochondria. In these cellular organelles several large protein complexes (I to V), embedded in the mitochondrial membrane, work in series in the respiratory chain to generate ATP. Complex I is the main entry point for metabolites and together with complexes III and IV it pumps protons across the mitochondrial membrane, which then drive complex V, or ATP synthase. Mutations in protein subunits of respiratory enzymes lead to a wide range of devastating human diseases. Reactive oxygen species production by complex I may be involved in Parkinson’s disease and aging.
Respiratory enzymes are huge by molecular standards: complex I is one of the largest known membrane proteins with a total mass of ~ 1Mega Dalton. Knowledge on the atomic structure of these gigantic molecular machines, performing fundamental cellular processes, is clearly needed to understand their mechanisms and to design drugs to treat related disorders.
Leonid A. Sazanov , together with his research group, determined the first atomic structures of several key respiratory enzymes. The overarching aim is to understand, on the basis of the structures, how these incredibly intricate and diverse molecular machines work. These discoveries transformed our knowledge about entire protein families, essential for life. Sazanov work now features in basic biochemistry and biology textbooks.
Due to its size, complex I presented a “grand challenge” of structural biology. Sazanov group first determined the structure of bacterial complex I, pushing the limits of X-ray crystallography. The structure established the intricate electron transfer pathway through the hydrophilic arm of complex I and a novel arrangement of several proton translocation pathways in the membrane arm. Mammalian complex I is much more elaborate – its core is conserved from bacteria but it is almost twice larger due to the presence of additional subunits. To provide appropriate model for understanding complex I-related human diseases, Sazanov group exploited latest revolutionary advances in cryo-electron microscopy (cryo-EM) and solved the first complete atomic structure of mammalian (ovine) enzyme. The structure revealed that additional “accessory” subunits form a stabilising shell around the conserved core and provide possible regulatory links to mitochondrial metabolism.
Specific problems recently solved by Sazanov group include:
1) The vast complexity of complex I that belies its efficiency is one of the most intriguing wonders in nature. Recent publications in Science (2020) and Nature (2022) proposed a first experiment-based detailed mechanism of coupling between electron transfer and proton translocation in complex I. It involves a completely unexpected combination of conformational changes and electrostatic interactions, and explains all the unusual features of complex I architecture.
2) In mammalian mitochondria the majority of respiratory complexes are actually found within even larger assemblies (supercomplexes). First structures of the respirasome (CICIII2CIV) and CIII2CIV provided implications for the regulation of the entire respiratory chain.
3) MRP cation/proton antiporters are related to the ancestor of complex I. MRPs are also needed for the survival of toxic microbes and so are important drug targets. The first structure of the MRP complex revealed features consistent with the Sazanov group proposal on the mechanism of complex I and related enzymes.
4) The first structure of the entire proton-translocating transhydrogenase led to the proposal of unusual, but robust molecular mechanism involving the rotations of the entire domains.
5) The first structure of the entire bacterial V/A-type ATPase allowed the description of its full catalytic cycle. The structure of mammalian F1Fo ATP synthase provided implications on the proton pathway and on possible involvement of this enzyme in its “moonlighting” role in cell death.
Leonid A. Sazanov studied biophysics at Belarusian State University Minsk and received his PhD from Moscow State University in 1990. He continued his research at Moscow State University's Belozersky Institute of Physico-Chemical Biology. In 1992, Leonid A. Sazanov received a fellowship from the Wellcome Trust and was postdoctoral researcher at the University of Birmingham (1992 to 1994) and research fellow at Imperial College London (1994 to 1997). From 1997 to 2015, he served as research associate at the Medical Research Council (MRC) Laboratory of Molecular Biology, Cambridge, and tenure-track research group leader, then tenured programme leader at MRC Mitochondrial Biology Unit, Cambridge. Since 2015, Leonid A. Sazanov is Professor of Structural Biology at the Institute of Science and Technology Austria in Klosterneuburg. He was elected a member of the European Molecular Biology Organization in 2018 and a Fellow of the Royal Society in 2019. Leonid A. Sazanov received an ERC Advanced Grant in 2021 and the Keilin Memorial Lecture and Medal 2022 of the Biochemical Society.