Our dear colleague Kiyoshi Nagai, an outstanding pioneer in the structural determination of RNA-protein complexes and the spliceosome, sadly passed away at the height of his career on September 27. After a PhD with Hideki Morimoto at Osaka University and a postdoc with Max Perutz at the MRC Laboratory of Molecular Biology (LMB) in Cambridge, he stayed at LMB for the rest of his life, working with a small group that focused with immense dedication on solving structures of the spliceosome using X-ray crystallography and cryo-electron microscopy. His monumental work includes the first glimpses of an RRM domain bound to its target RNA, of U1 snRNP, U4/5/6 tri-snRNP as well as spliceosome complexes from pre- to post-catalytic. His smiling face will always come to mind when we reveal something new and beautiful about the RNA World.
While recent spliceosomal structures have dazzled us with their mechanistic complexity, our first glimpse of spliceosomal architecture was provided in 1990, when Kiyoshi Nagai published the first high resolution structure of a spliceosomal protein in isolation (U1A, Nagai, Nature 1990) and then in complex with its RNA receptor (U1A/U1 hairpin RNA, Oubridge, Nature 1994), linking these reports with function by elucidating the basis for RNA sequence recognition by an RRM domain (Price et al Nature 1998). These landmark findings set the stage for Dr. Nagai’s long and determined quest to understand the molecular basis for RNA splicing. Tragically, at the height of his career, we lost Kiyoshi Nagai to cancer on September 27, just as he and his team were solving structures that will elucidate the critical mechanisms for control and regulation of pre-mRNA splicing.
Over the years, Dr. Nagai carefully tugged on strands of the spliceosome, methodically unraveling its architecture and revealing its behaviors with a scientific style that combined both creativity and scientific rigor. His early work on “SM ring” complexes, together with meticulous studies of RNA folding and complex assembly, lay the groundwork for structural analysis of individual snRNP particles, culminating in the first high resolution glimpses of U1 snRNP (Pomeranz Krummel, Nature 2009) and the U4 snRNP core domain (Leung, Nature 2011). At last, it was possible to visualize the building blocks for the eukaryotic spliceosome.
A critical milestone in spliceosome structural biology was provided by Dr. Nagai in 2015, when he and his colleagues solved the cryo-EM structure of the U4/U6/U5 tri-snRNP complex, which is the heart of the spliceosomal apparatus (Nguyen, Nature 2015 and 2016). This structure demonstrated that high resolution information on the spliceosome was attainable and that cryo-electron microscopy (cryo-EM) would be the key technology for achieving this goal. Dr. Nagai, Dr. Yigong Shi and Dr. Reinhard Luhrmann went on to solve more complete structures of the spliceosome at critical stages of the catalytic cycle and at various stages of assembly. Most recently, Dr. Nagai and his team visualized human spliceosomes in complex with alternative splicing factors (Fica, Science 2019). And true to his roots, Dr. Nagai’s recent papers on pre-spliceosomes (Plaschke, Nature 2018 ; Charenton, Science 2019) have provided key insights into the dynamic process of spliceosome assembly.
Although Dr. Nagai grew up in Osaka, Cambridge and the Laboratory of Molecular Biology became his home. There, he maintained a small group that focused with immense dedication on solving structures of the spliceosome. Dr. Nagai’s success was propelled, in large part, by his skills as a supportive mentor of students and postdocs, who felt emboldened to take on projects that seemed impossible at the time. Dr. Nagai was also an enthusiastic mentor of young faculty worldwide. We looked to him for advice on our projects, and we looked to him as an example: as someone who could identify great scientific problems, and then tackle them tenaciously, come what may. We will remain inspired by his accomplishments, and motivated to emulate his dedication to the scientific community.