Emeritus Professor Keiichiro Hashimoto. Until his retirement leader of the Biopolymer group at the Institute for Comprehensive Medical Science at Fujita Health University
In December 2021, our research group led by Professor Keiichiro Hashimoto, who retired in 2020 but kept working on this important study, had an article published in PNAS. The study was supported by Prof. Geert Wiegertjes in the Netherlands and Prof. Unni Grimholt in Norway as co-authors.
The article, by Omakura et al., is titled Discovery of an ancient MHC category with both class I and class II features and describes the discovery of an ancient group of major histocompatibility complex (MHC) molecules. Genes for these molecules were found in sharks, ray-finned fishes, lungfishes, coelacanths, and salamanders. This newly discovered MHC group, called “W” after a characteristic tryptophan, consists of two similar-sized transmembrane molecules like MHC class II, but is phylogenetically closer to and has interdomain motifs as in MHC class I (see Figs. 3 and 4). The study concludes that, in evolution, MHC class II came before MHC class I, and that several characteristic features of the small MHC class I component β2-m are not related to it being a soluble molecule but probably have a, still unknown, mechanistic function that can also work in an MHC class II type arrangement. Okamura et al. propose, logically, that in evolution MHC class I emerged from a W molecule.
Professor Peter Parham of Stanford University has called it a landmark study, and Professor Jim Kaufman of Edinburgh University (before Cambridge University) called it the first advance in many decades for understanding the early evolution of MHC genes (see our Press Release). PNAS has selected the article for highlighting “IN THIS ISSUE” (Fig. 2) and also for inviting a Commentary article (to describe its importance for non-specialists) by Prof. Jim Kaufman. The Commentary article title is The new W family reconstructs the evolution of MHC genes (Fig. 3).
I have no intention to use this blog for highlighting publications. This is an exception. Hashimoto-sensei has been a great boss for 16 years, always giving me almost complete freedom, and always caring, before anything else, about the well-being of his staff and research integrity. It was a great joy to work with him. This paper is his life work, with the first hints for the now proven scenario already obtained almost 30 years ago by his study in 1992, also in the journal PNAS. In the modern field of MHC evolution, I can’t think of a bigger possible finding than revealed in this new Okamura et al. publication. Nowadays, MHC evolution is not a very big or popular research field, and I am so glad that Prof. Hashimoto got the honor his work deserves.
Figure 2. The PNAS Dec 21 issue highlighted the Okamura et al. paper in their section “IN THIS ISSUE.” They added a picture of sharks, as W genes were found in these species.
Figure 3. By request of PNAS, Prof. Jim Kaufman wrote a commentary article to accompany the Okamura et al. article so that non-specialists can more easily understand its importance: Kaufman J. The new W family reconstructs the evolution of MHC genes. Proc Natl Acad Proc Natl Acad Sci U S A. 2022 Feb 1;119(5):e2122079119. The article includes this beautifully elegant summary figure of the findings in the Okamura et al. article and has as legend: “Proposed evolutionary scenario from the ancestral molecule to class II and W molecules, with subsequent evolution from W molecules to class I molecules. The ancestral, class II, and W molecules all have two chains of roughly equal size (α-chain in blue, β-chain in green, membrane in yellow), while the class I molecule has rearranged the domains (β2-m in blue, heavy chain in blue and then green). The ancestral molecule has nearly invariant tryptophans between the β-sheets of both membrane-proximal Ig-C domains (W in gray), which are maintained in the class II molecule but are replaced by other hydrophobic residues in the W α2 domain and β2-m. Among the other changes are tryptophans involved in interdomain interaction (W in black): one in the β2 domain of class II molecules and ones in the W α2 domain and β2-m.”
Figure 4. This figure was used in our Press Release. The newly discovered MHC class W molecules show characteristics of an intermediate in MHC class diversification. While MHC-W possesses alpha and beta genes as in MHC-II, it exhibits interdomain motifs as in MHC-I to which it is phylogenetically close. Regarding the leader (L) and transmembrane and cytoplasmic regions (TM/CY) the nature of the exon shuffling event that created MHC-I is not known yet. The depicted structures are from HLA-A2 (PDB 3PWN) and HLA-DR1 (PDB 1AQD). The figure essentially tells the same story as above in Fig. 3, but shows some more structural details and also the intron-exon level organization. In our press release, to keep it simple, we did not highlight that the W-α2 domain, similar to β2-m in MHC class I, lost the type of hydrophobic core that is standard to the immunoglobulin domain superfamily (IgSF) to which they belong. For specialists among the readers here: For a better appreciation of this change in IgSF domain core between MHC classes I and II, see Fig. 11 in Wu et al. 2021.
This is a summary of the curriculum vitae (CV) of Prof. Martin Oudega, Professor of Physical Therapy and Human Movement Sciences & Neuroscience, Northwestern University, Chicago, USA
. He will give a presentation at Fujita Health University.
This is a summary of the curriculum vitae (CV) of Dr. Yasumasa Ishida, M.D., Ph.D., Independent Associate Professor, Laboratory of Functional Genomics and Medicine, Division of Biological Sciences, Graduate School of Science and Technology, Nara Institute of Science and Technology, Nara, Japan. He will give a presentation at Fujita Health University.
