Tissue-specific functional studies on calpains

• Project/Area Number: 23247021
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Functional biochemistry
• Research Institution: Tokyo Metropolitan Institute of Medical Science
• Principal Investigator: SORIMACHI Hiroyuki 公益財団法人東京都医学総合研究所, 生体分子先端研究分野, 分野長 (10211327)
• Co-Investigator(Renkei-kenkyūsha): ONO Yasuko 公益財団法人東京都医学総合研究所, 生体分子先端研究分野, 主席研究員 (20392376) ; HATA Shoji 公益財団法人東京都医学総合研究所, 生体分子先端研究分野, 主席研究員 (10392375) ; MATSUOKA Kunie 公益財団法人東京都医学総合研究所, ゲノム医科学研究分野, 主席研究員 (40291158) ; TONAMI Kazuo 公益財団法人東京都医学総合研究所, 生体分子先端研究分野, 研究員 (70511393)
• Project Period (FY): 2011-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥26,780,000 (Direct Cost: ¥20,600,000、Indirect Cost: ¥6,180,000); Fiscal Year 2013: ¥13,390,000 (Direct Cost: ¥10,300,000、Indirect Cost: ¥3,090,000); Fiscal Year 2012: ¥13,390,000 (Direct Cost: ¥10,300,000、Indirect Cost: ¥3,090,000)
• Keywords: カルパイン / プロテオリシス / 質量分析 / 筋ジストロフィー / 胃腸疾患 / 自己消化 / 酵素学 / 基質特異性 / 組織特異的発現 / 遺伝子改変マウス

Outline of Final Research Achievements

Calpains (CAPNs) are intracellular proteases that modulate substrate proteins by limited proteolysis. Although CAPN1/2 have well been studied so far, their physiological functions are still elusive because of their ubiquitous expression profiles.We have identified several tissue-specific calpains, and analyzed their functions in relation to the functions of the tissues where they are expressed. As a result, we revealed that defects of CAPN3 proteolytic activity cause muscular dystrophy, and that deficiencies of CAPN8/9 result in stress-induced gastric ulcer. Furthermore, other tissue-specific calpains were analyzed in terms of tissue functions. Proteomic analysis suggested that several novel substrates of these new members of calpains play important roles on pathophysiology of calpain-deficient diseases, "calpainopathies".

Research Products

• [Journal Article] The N- and C-terminal autolytic fragments of CAPN3/p94/calpain-3 restore proteolytic activity by intermolecular complementation. (2014)
  • Author(s): Ono, Y., Shindo, M., Doi, N., Kitamura, F., Gregorio, C. C., and Sorimachi, H.
  • Journal Title: Proc. Natl. Acad. Sci. U. S. A. Volume: 111 Issue: 51
  • DOI: 10.1073/pnas.1411959111
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Calpain-6 deficiency promotes skeletal muscle development and regeneration. (2013)
  • Author(s): Tonami, K., Hata, S., Ojima, K., Ono, Y., Kurihara, Y., Amano, T., Sato, T., Kawamura, Y., Kurihara, H., Sorimachi, H.
  • Journal Title: PLOS Genetics Volume: 9 Issue: 8 Pages: 1003668-1003668
  • DOI: 10.1371/journal.pgen.1003668
  • Peer Reviewed / Open Access
• [Journal Article] Regulation and physiological roles of the calpain system in muscular disorders (2012)
  • Author(s): Sorimachi, H., Ono, Y
  • Journal Title: Cardiovasc. Res Volume: 96 Issue: 1 Pages: 11-22
  • DOI: 10.1093/cvr/cvs157
  • Peer Reviewed
• [Journal Article] Understanding the substrate specificity of conventional calpains (2012)
  • Author(s): Sorimachi, H., Mamitsuka, H., Ono, Y
  • Journal Title: Biol. Chem Volume: 393 Issue: 9 Pages: 853-871
  • DOI: 10.1515/hsz-2012-0143
  • Peer Reviewed
• [Journal Article] Calpains - An elaborate proteolytic system (2012)
  • Author(s): Ono Y, Sorimachi H
  • Journal Title: Biochim Biophys Acta Volume: 1824 Issue: 1 Pages: 224-236
  • DOI: 10.1016/j.bbapap.2011.08.005
  • Peer Reviewed
• [Journal Article] Non-proteolytic functions of calpain-3 in sarcoplasmic reticulum in skeletal muscles. (2011)
  • Author(s): Ojima K, Ono Y, Ottenheijm C, HataS, Suzuki H, Granzier H, Sorimachi H
  • Journal Title: J Mol Biol Volume: 407 Issue: 3 Pages: 439-449
  • DOI: 10.1016/j.jmb.2011.01.057
  • Peer Reviewed
• [Journal Article] Calpain chronicle--an enzyme family under multidisciplinary characterization. (2011)
  • Author(s): Sorimachi, H.
  • Journal Title: Proc Jpn Acad Ser B Phys Biol Sci Volume: 87 Pages: 287-327
  • NAID: 130000903736
  • Peer Reviewed
• [Journal Article] Impact of genetic insights into calpain biology. (2011)
  • Author(s): Sorimachi, H.
  • Journal Title: Journal of Biochemistry Volume: 150 Pages: 23-37
  • DOI: 10.1016/b978-0-12-382219-2.00458-0
  • NAID: 10030586192
  • ISBN: 9780123822192
  • Peer Reviewed
• [Journal Article] Does the severity of the LGMD2A phenotype in compound heterozygotes depend on the combination of mutations? (2011)
  • Author(s): Saenz A, Ono Y, Sorimachi H, Goicoechea M, Leturcq F, Blazquez L, Garcia-Bragado F, Marina A, Poza JJ, Azpitarte M, Doi N, Urtasun M, Kaplan JC, Lopez de Munain A
  • Journal Title: Muscle and Nerve Volume: 44 Issue: 5 Pages: 710-714
  • DOI: 10.1002/mus.22194
  • Peer Reviewed
• [Presentation] Extended concept for calpain “activity” – non-proteolytic functions of unconventional calpains. (2013)
  • Author(s): Sorimachi, H., Tonami, K., Shinkai-Ouchi, F., Hata, S., Ojima, K., and Ono, Y.
  • Organizer: FASEB Summer Research Conferences – Biology of Calpains in Health & Disease
  • Place of Presentation: Vermont, USA.
  • Year and Date: 2013-07-21 – 2013-07-26
  • Invited
• [Presentation] カルパイン機能不全と疾患 Calpains in health and disease (2013)
  • Author(s): 反町洋之、秦勝志、礪波一夫、大内史子、小野弥子
  • Organizer: 日本薬学会第133回年会
  • Place of Presentation: 横浜
  • Invited
• [Presentation] Towards understanding the enigmatic substrate specificity of calpains (2012)
  • Author(s): Sorimachi, H., duVerle, D., Hata, S., Tonami, K., Ouchi, F., Ojima, K., Takigawa, I., Mamitsuka, H. and Ono, Y.
  • Organizer: XIIIth Symposium on Proteases, Inhibitors and Biological Control
  • Place of Presentation: Portoroz, Slovenia
  • Invited
• [Presentation] Calpin-3 and connectin/titin as physical stress sensor system for skeletal muscle. (2012)
  • Author(s): Sorimachi, H.
  • Organizer: 4th Sensing Biology Symposium
  • Place of Presentation: Tokyo
  • Invited
• [Presentation] Muscle-specific calpain modulates stress response in muscle cells. (2012)
  • Author(s): Sorimachi, H.
  • Organizer: The 3rd Japan-Korea Joint Symposium on Life Science
  • Place of Presentation: Tokyo
  • Invited
• [Remarks] Calpain Research Portal Site
  • URL: http://calpain.net/
• [Remarks] Calpain for Modulatory Proteolysis Database
  • URL: http://calpain.org/
• [Remarks] Calpain Project Web Site
  • URL: http://www.igakuken.or.jp/project/detail/calpain.html
• [Remarks] Calpain Research Portal Site
  • URL: http://www.calpain.net/
• [Remarks] Calpain for Modulatory Proteolysis Database
  • URL: http://www.calpain.org/
• [Remarks] 公益財団法人 東京都医学総合研究所 カルパインプロジェクト ウェッブサイト
  • URL: http://www.igakuken.or.jp/calpain/
• [Remarks] Calpain Research Portal Site
  • URL: http://www.calpain.net/
• [Remarks] 公益財団法人 東京都医学総合研究所 カルパインプロジェクト ウェッブサイト
  • URL: http://www.igakuken.or.jp/calpain/