Biological modulation by calpain proteolysis

2008 Fiscal Year Self-evaluation Report

• Project Area: Proteolysis in the Regulation of Biological Processes
• Project/Area Number: 18076007
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: 財団法人東京都医学研究機構 (2010); Tokyo Metropolitan Organization for Medical Research (2006-2009)
• Principal Investigator: SORIMACHI Hiroyuki Tokyo Metropolitan Organization for Medical Research, 東京都臨床医学総合研究所, 副参事研究員 (10211327)
• Project Period (FY): 2006 – 2010
• Keywords: カルパイン / 胃腸 / 酵素 / プロテオリシス / カルシウム / メンブレン・トラフィック / 骨格筋

Research Abstract

カルパインは細胞質内に存在し、厳密に基質を認識して限定分解する、Ca2+-要求性モジュレータ・プロテアーゼである。哺乳類のカルパイン15 遺伝子の約半数について、その変異により疾患・致死の引き起こされることが明らかとなっている。よって、カルパインが生体の正常な維持に必須な酵素であることが明確となっている。ヒトのカルパイン不全による疾患には筋ジストロフィー、糖尿病などが含まれ、カルパインを標的とした診断・治療の期待が高まっている。一方で、カルパインの作用機序ついては未だにほとんどが不明である。そこで本研究では、カルパインの作用機序を個体、細胞、in vitro の各レベルから解析し、カルパイン不全による生体システム破綻のメカニズムを明確にし、カルパインが生体をモジュレートする分子機構の解明を目的とした。

Research Products

• [Journal Article] Multiple molecular interactions implicate connectin/titin N2A region as a modulating scaffold for p94/calpain 3 activityin skeletal muscle (2008)
  • Author(s): Hayashi, C., Ono, Y., Doi, N., Kitamura, F., Tagami, M., Mineki, R., Arai, T., Taguchi, H., Yanagida, M., Hirner, S., Labeit, D., Labeit, S., Sorimachi, H
  • Journal Title: J. Biol. Chem 283 Pages: 14801-14814
  • Peer Reviewed
• [Journal Article] The importance of conserved amino acid residues in protease sub-domain IIb and the IS2 region in p94 for constitutive autolysis (2008)
  • Author(s): Ono, Y., Hayashi, C., Doi, N., Tagami, M., Sorimachi, H
  • Journal Title: FEBS Lett 582 Pages: 691-698
  • Peer Reviewed
• [Journal Article] Muscle RING-finger protein MuRF1 as a connector of muscle energy metabolism and protein synthesis (2008)
  • Author(s): Koyama, S., Hata, S., Witt, C. C. , Ono, Y., Lerche, S., Ojima, K., Chiba, T., Doi, N., Kitamura, F., Tanaka, K., Abe, K., Witt, S., Rybin, V., Gasch, A., Franz, T., Labeit, S., Sorimachi, H
  • Journal Title: J. Mol. Biol 376 Pages: 1224-1236
  • Peer Reviewed
• [Journal Article] Stomach-specific calpain, nCL-2/calpain 8, is activewithout calpain regulatory subunit, and oligomerizes through C2-like domains (2007)
  • Author(s): Hata, S., Doi, N., Kitamura, F., Sorimachi, H
  • Journal Title: J. Biol. Chem 282 Pages: 27847-27856
  • Peer Reviewed
• [Journal Article] Myogenic stage, sarcomere length and protease activity modulate localization ofmuscle-specific calpain (2007)
  • Author(s): Ojima, K., Ono, Y., Doi, N., Yoshioka, K., Kawabata, Y., Labeit, S., Sorimachi, H
  • Journal Title: J. Biol. Chem 282 Pages: 14493-14504
  • Peer Reviewed
• [Journal Article] Comprehensive survey of p94/calpain 3 substrates by comparative proteomics - Possible regulation of protein synthesis by p94 (2007)
  • Author(s): Ono, Y., Hayashi, C., Doi, N., Kitamura, F., Shindo, M., Kudo, K., Tsubata, T., Yanagida, M., Sorimachi, H
  • Journal Title: Biotech. J 2 Pages: 565-576
  • Peer Reviewed
• [Journal Article] Suppressed disassembly of autolyzing p94/CAPN3 in a genetic reporter system (2006)
  • Author(s): Ono, Y., Torii, F., Ojima, K., Doi, N., Yoshioka, K., Kawabata, Y., Labeit, D., Labeit, S., Suzuki,K., Abe, K., Maeda, T., Sorimachi, H
  • Journal Title: J. Biol. Chem 281 Pages: 18519-18531
  • Peer Reviewed
• [Journal Article] Stomach-specific calpain, nCL-2, localizes in mucus cells and proteolyzes the β-subunitof coatomer complex (2006)
  • Author(s): Hata, S., Koyama, S., Kawahara, H., Doi, N., Maeda, T., Toyama-Sorimachi, N., Abe, K., Suzuki, K., Sorimachi, H
  • Journal Title: β-COP. J. Biol. Chem 281 Pages: 11214-11224
  • Peer Reviewed
• [Presentation] Roles of skeletal muscle-specific calpain, p94/calpain 3, on multiple molecular interactions using connectin/titin N2A region as a modulating scaffold (2008)
  • Author(s): Sorimachi, H
  • Organizer: 11th International Symposium on PROTEINASE INHIBITORS AND BIOLOGICAL CONTROL
  • Place of Presentation: Portoroz, Slovenia
  • Year and Date: 2008-09-02
• [Presentation] La calpaina como "proteina moduladora" en la enfermedad y la salud. (Calpain as a "modulator protease" in health and muscle disease.) (2008)
  • Author(s): Sorimachi, H
  • Organizer: UPV/EHU (Universidad del Pais Vasco/Euskal Herriko Unibertsitatea) Summer Course Symposium: Distrofias por Deficit de Calpaina-3: Una Vision General
  • Place of Presentation: San Sebastian, Spain
  • Year and Date: 2008-07-14
• [Presentation] Analysis of structure-function relationships of p94 by proteinase-trapping system (2008)
  • Author(s): Ono, Y
  • Organizer: The Joint 4th AOHUP (Asian Oceania Human Proteome Organisation) and 2nd PRICPS (Pacific Rim International Conference on Protein Science)
  • Place of Presentation: Cairns, Australia
  • Year and Date: 2008-06-22
• [Presentation] Toward Understanding Relationships between Proteolytic Activity of Skeletal Muscle-Specific Calpain and Calpainopathy (2007)
  • Author(s): Sorimachi, H
  • Organizer: 2007 Korea-Japan Joint Symposium "Protein Modification and Degradation in Human Diseases"
  • Place of Presentation: Seoul, South Korea
  • Year and Date: 2007-09-05
• [Presentation] Unconventional calpains. FASEB Summer Research Conferences (2007)
  • Author(s): Sorimachi, H
  • Organizer: The Biology of Calpains in Health & Disease
  • Place of Presentation: Colorado, USA
  • Year and Date: 2007-07-15
• [Presentation] Novel approaches for analysis of proteolytic activity of muscle-specific calpain p94/calpain 3 (2007)
  • Author(s): Sorimachi, H
  • Organizer: Xth International Symposium on PROTEINASE INHIBITORS AND BIOLOGICAL CONTROL: From single molecules to degradomics
  • Place of Presentation: Portoroz, Slovenia
  • Year and Date: 2007-06-24
• [Remarks] 研究室ホームページ:
  • URL: http://www.rinshoken.or.jp/ER/