Lührmann, R.

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Kiyoshi Nagai (1949–2019)Kiyoshi Nagai, group leader at the MRC Laboratory ofMolecular Biology Cambridge, UK, sadly passed away onSeptember 27, 2019 at the age of 70.Kiyoshi grew up in Osaka, Japan and was trained as abiophysicist at Osaka University. He received his Doctorof Philosophy in 1977 under the supervision of ProfessorHideki Morimoto, working on allosteric effects in hemo-globin. During his PhD work, Kiyoshi spent 18 months atthe LMB in the group of Max Perutz. After four years asAssistant Professor at Nara Medical School, Japan,Kiyoshi returned to the LMB, to which he devoted the re-mainder of his scientific life. In 1984 he was appointed asa group leader in the Structural Studies division, and wasjoint head of this division from 2001 to 2010.Kiyoshi was a brilliant biophysicist, who pioneered thestructural biology of the spliceosome, the molecular ma-chine that catalyzes the removal of introns from nuclearpre-mRNAs. The major building blocks of the spliceo-some—the snRNPs U1, U2, U4/U6, and U5, and numerousadditional proteins—assemble anew onto each pre-mRNAintron that needs to be spliced out. This follows a sophisti-cated assembly-line process, in which a succession of dis-tinct RNP complexes is generated during each round ofpre-mRNA splicing. Thus the spliceosome is an extremelydynamic molecular machine; its composition and structurechange continuously during its life cycle, presenting a tre-mendous challenge for determining and understanding itsstructure. Kiyoshi tackled this demanding task with amaz-ing perseverance, creativity, and scientific rigor. He pub-lished the first crystal structure of the RNA recognitionmotif (RRM) of the U1A protein in 1990, which was fol-lowed soon after by the crystal structures of the U1ARRM in complex with the stem–loop II of U1 snRNA andof the ternary complex of the U2 proteins A′ and B′′ togeth-er with the U2 snRNA stem–loop IV. Collectively, thesestructures provided important insight into a fascinatingmechanism of RNA recognition. At the same time, thesesuccesses catapulted Kiyoshi to prominence in the grow-ing and exciting field of RNA–protein interactions.In a tour de force, Kiyoshi and his group succeeded inexpressing recombinantly several pairs of the seven Smproteins that make up the core of the spliceosomalsnRNPs, and by solving the structure of the SmD1–SmD2and SmB–SmD3 protein complexes, in 1999 Kiyoshicame up with the ingenious idea that the seven Sm pro-teins would form a doughnut-shaped Sm core structure.Some ten years later, by solving the structures of the U4snRNP core domain and that of recombinantly producedU1 snRNP, his group not only showed that this modelwas correct, but also that the Sm site RNA is threadedthrough the inner hole of the Sm doughnut, revealing anovel type of protein–RNA interaction.Kiyoshi’s group was also at the forefront of solving thestructure of the U5 snRNP proteins. For example, they crys-tallized the large domain of Prp8 in 2013, the major scaf-folding protein of the spliceosome that contacts all thereactive sites of the pre-mRNA intron in the spliceosome.This structure also revealed the first glimpse into whichpart of Prp8 could be located close to the site on the spli-ceosome that accommodates the catalytic RNA.A few years ago, a “resolution revolution” took place inthe cryo-EM field, thanks mainly to dramatic improve-ments in detector hardware and computer software. Thisallowed the reconstruction of high-resolution 3D structuresof large molecular machines, even those as dynamic as thespliceosome. A few years ago, Kiyoshi was the first to pub-lish cryo-EM structures of the S. cerevisiae U4/U6.U5 tri-snRNP, the largest building block of the spliceosome,which in turn provided insight into many other novel pro-tein–protein and protein–RNA interactions. Kiyoshi thenwent on to publish the cryo-EM structures of catalyticallyactive yeast spliceosomes that were stalled immediately af-ter the first catalytic step and before the second catalyticstep, as well as a postcatalytic spliceosome, in which thepre-mRNA intron was excised and exons were ligated.Among other things, these structures provided insight(Photo courtesy of Song Tan)RNA (2020) 26:vii–viii; Published by Cold Spring Harbor Laboratory Press for the RNA Society vii Cold Spring Harbor Laboratory Press on January 22, 2020 - Published by rnajournal.cshlp.orgDownloaded from into the dramatic remodeling of the spliceosome duringthe catalytic phase, and showed that the spliceosome in-deed uses a single catalytic center for carrying out bothcatalytic steps of pre-mRNA splicing. Very recently,Kiyoshi also determined the structure of earlier assemblystages of the yeast spliceosome and a human P complex,which revealed the likely roles of metazoan-specific splic-ing factors in the ligation process.Although my group and that of Dr. Yigong Shi (atTsinghua University, Beijing) were Kiyoshi’s competitors,publishing additional and/or complementary cryo-EMstructures of various spliceosomal snapshots from yeastand human, Kiyoshi never let this get in the way of our per-sonal and scientific relationships. Our interactions re-mained characterized by friendship, openness, andmutual respect, which speaks volumes about Kiyoshi’scharacter and human stature. Collectively, within an amaz-ingly short period, a long-cherished dream that we allshared has come true:We have not only obtained an atom-ic-level model of the spliceosome’s catalytic center, buthave also gained insight into the striking gymnastics thatmany of the spliceosomal factors perform during the splic-ing cycle. Kiyoshi’s structural work was instrumental inachieving this long sought after goal in the pre-mRNAsplicing field. It is therefore all the more tragic thatKiyoshi passed away at the height of his scientific careerand could enjoy the beauty of his wonderful discoveriesfor only such a short time.With Kiyoshi’s passing, the RNA community has lost notonly a brilliant and inspiring scientist, but also a wonderfulcolleague, who was thoughtful, conscientious, generous,and highly dedicated to serving the scientific community.More than this, Kiyoshi was also a respected mentor whocared tremendously about the training and future careersof his students and post-docs. Indeed, only about a weekbefore Kiyoshi passed away he sent me an e-mail askingme to write a letter in support of an application by oneof his post-docs.We will miss Kiyoshi greatly, but we will always remem-ber his smiling face, his warm personality, and his respectand support for others.Reinhard LührmannMax Planck Institute for Biophysical Chemistry37077 GöttingenGermanyIn memoriamviii RNA (2020) Vol. 26, No. 2 Cold Spring Harbor Laboratory Press on January 22, 2020 - Published by rnajournal.cshlp.orgDownloaded from  10.1261/rna.074021.119Access the most recent version at doi: 2020 26: vii-viii originally published online November 15, 2019RNA  Reinhard Lührmann  2019)−Kiyoshi Nagai (1949  LicenseServiceEmail Alerting   click here.top right corner of the article or Receive free email alerts when new articles cite this article - sign up in the box at the http://rnajournal.cshlp.org/subscriptions go to: RNATo subscribe to Published by Cold Spring Harbor Laboratory Press for the RNA Society Cold Spring Harbor Laboratory Press on January 22, 2020 - Published by rnajournal.cshlp.orgDownloaded from 

Kiyoshi Nagai (1949-2019).

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