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Impact Objectives Impact Objectives • Develop a better understanding of the molecular mechanisms of calpainopathies by investigating the physiological functions of calpains • Clarify the physiological functions of calpains • Delve deeper into the complexities of calpain molecules as a means of ultimately developing effective drugs and therapies for calpain-related diseases Insights into the complex world of calpains The CALPAIN project is investigating the role of calpains in basic cellular functioning and disease development. Here Dr Hiroyuki Sorimachi discusses his ongoing research and addresses uncertainties around calpains Could you give a Some calpain substrate proteins play on several disease symptoms. Many actions brief explanation important roles in cytoskeletal remodelling, of calpains have been left in a black box. It of what a calpain cell growth, signal transductions for cell cycle is our role to understand and decrease the is and the regulation and stress responses (adaptation). contents of such a black box. background and key For example, it has been suggested CAPN3 is goals behind the involved in stress responses to boost muscle In line with this, the principle of our project CALPAIN project? adaption, and malfunction of CAPN3 by allows us to study calpains as a family of genetic mutation causes muscular dystrophy. protease, providing us with the general A calpain is an intracellular Ca2+-dependent Another example is Eosinophilic oesophagitis, impression. Since some calpain species have protease and is involved in diverse aspects caused by a deficiency of CAPN14, which diverged structures and/or functions, an of cellular functions. Calpain homologs regulates immune response in esophagus. important finding may come from a different exist in almost all eukaryotes and constitute In addition, our study using KO (knockout) direction. We hope our approach will help to a super-family. For human and mouse mice suggests that some gastric dysfunction determine how to appreciate such a spin-off. calpains, genetic defects cause various is linked to insufficient activity of CAPN8 deficiencies, termed calpainopathies. and CAPN9 complex, and that deprivation What is next for your research in the coming of CAPN6 makes muscles slightly bigger. five to 10 years? The CALPAIN project constitutes one of the research activities at the Tokyo Metropolitan On the other hand, hyperactivation of Thanks to genome sequencings, calpain Institute of Medical Science, Japan. Our project calpains can also be a type of malfunction. sequences from various living organisms specifically aims to understand molecular For example, excess activity of CAPN5 is have been revealed. I think now is the time mechanisms of calpainopathies. We investigate causative for vitreoretinopathy. to think about evolutionary aspects of calpain physiological functions of calpains in three key molecules. Precise structural comparison of areas: biological consequences of calpain- There are several diseases that do not stem calpains from various organisms will shed mediated proteolysis of substrates; regulation from calpain malfunction (neurodegenerative light on structure-function relationships of of calpain activity; and substrate specificities. disorders, ischemia of the brain and the heart, this molecule. This approach may ultimately myopathies, cancers), but the symptoms of answer the questions; what are calpains, Although there are some human calpain which are exacerbated by calpain activities. and why are they (not) required for living species we specifically focus on, we try to These relationships are derived from the organisms? keep any calpain species within the scope fact calpain substrates are involved in the of our interest. We intend to transform our above-mentioned biological processes. As long as the situations surrounding the research outcome into more concrete basic research permits, I would like to continue the knowledge about calpains, and support Can you explain the importance of this work way we have been conducting our research, the development of therapeutic means in real-world terms? thereby focusing on the molecule/calpain for correcting aberrant calpain functions of interest. Identification of substrates and manifested as calpainopathies. I would like to update the general concept nailing down the one (or some), which surrounding calpains as much as possible. are critical for the phenotype of KO mice, What biological processes are calpains linked In the past, the outcomes of calpain will be a great achievement for us and will to and what diseases can arise from their research have been appreciated based on allow us to eventually think about the malfunction? the beneficial effects of calpain inhibition evolutionary importance of calpains. 74 www.impact.pub Illustration by Unravelling the calpain Emiko Wakatsuki The CALPAIN project aims to unravel the complexity of calpain molecules and, in turn, use their discoveries to generate effective drugs and therapies for calpain-related diseases In an effort to further scientific understanding engaged with the structure-function relationships housekeeper is well known, their mechanistic of calpains and their vital biological roles, the and substrate specificities of calpains. features are still poorly understood. To address CALPAIN project was established within the this issue, one of the CALPAIN project’s Tokyo Metropolitan Institute of Medical Science Along with studying the basic structure and main objectives is to recognise calpains as: in Japan. Led by Department Head Dr Hiroyuki function of a calpain, researchers are working ‘a word representing the family of enzymes, Sorimachi, the CALPAIN project’s goals include to unravel the molecular mechanisms behind rather than just the conventional calpains,’ analysing the mechanisms of calpains at a calpain-related diseases. By discovering the Sorimachi explains. molecular level; clarifying their physiological pathology of these diseases, members of the functions; analysing diseases marked by CALPAIN project can aid in the development So far, scientists have discovered that calpain deficiency using genetically-modified of novel strategies for predicting, preventing, humans have 15 calpain genes. Two of these mice; and developing future diagnosis and diagnosing and treating various disorders. genes, CAPN1 and CAPN2, are known as treatment plans for calpain-related diseases. conventional calpains, as they are the most AN ENIGMATIC ENZYME ubiquitous and well-studied sub-units. Yet Sorimachi’s career began in the late Dr Koichi Originally discovered in 1964 by noted there are also unconventional classical Suzuki‘s lab, which was dedicated to studying biochemist Gordon Guroff, calpains are a super- and unconventional non-classical calpain and cloning calpains. With the help of family of proteases that are expressed in almost types. Unconventional classical calpains his colleagues, Suzuki became a pioneer all eukaryotes and bacteria. The term ‘protease’ are molecules with an identical structure to within the field by discovering the complete refers to the main function of a calpain – to CAPN1 and CAPN2, but a different function. primary structure of a calpain. Since then, perform proteolysis and breakdown substrates The unconventional non-classical calpains are the CALPAIN project has grown significantly into smaller polypeptides and amino acids. the most dissimilar group, as their structures and now includes: Associate Director Dr However, unlike most other proteases, calpains diverge from conventional calpains. Yasuko Ono who is particularly interested in have limited proteolytic activity. As opposed investigating the function of CAPN3/calpain-3 in to completely breaking the substrates down, Until the late 1980s, scientists believed that muscle tissues; Chief Researcher Dr Shoji Hata the calpain modulates the substrates’ function CAPN1 and CAPN2 were the only calpain whose focus lies with the physiological function and structure. Thus, calpains have earned the species. However, since the CALPAIN project of mammalian calpains that have specific name ‘modulator proteases’. The modulation of discovered CAPN3 in 1989, unconventional structures or expressions; and Senior Researcher substrates is an essential intracellular process. calpains have become a hot topic in the field. Dr Fumiko Shinkai-Ouchi, who explores dynamic Calpains have a vital role to play and any It has been demonstrated that they can be modulation of protein, including calpain itself, deficiency can lead to major medical issues. intriguing molecules that offer researchers as readout of calpain functions by proteomic a greater insight into calpains’ physiological approach. Sorimachi meanwhile, is currently Although the role of a calpain as a cellular functions and calpain-related diseases. www.impact.pub 75 Functional calpains allow cells to function like well-oiled machines. When a calpain malfunctions, diseases called ‘calpainopathies’ arise DEFICIENT CALPAINS Project Insights Along with trying to label calpain sub-units, researchers are also interested in the effect FUNDING This research is supported by JSPS of deficient calpains on biological systems. KAKENHI, Takeda Science Foundation Research Grant and the Cross-ministerial Functional calpains allow cells to function like Strategic Innovation Promotion Program. well-oiled machines. However, when a calpain malfunctions, diseases called ‘calpainopathies’ It has also received the following funding: can arise. Calpainopathies can result from Open Partnership
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