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Functional analysis of digestive tract-specific calpains in terms of functional foods.

Research Project

Project/Area Number 18380085
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Food science
Research InstitutionTokyo Metropolitan Organization for Medical Research

Principal Investigator

SORIMACHI Hiroyuki  Tokyo Metropolitan Organization for Medical Research, the Tokyo Metropolitan Institute of Medical Science, 副参事研究員 (10211327)

Project Period (FY) 2006 – 2007
Project Status Completed (Fiscal Year 2007)
Budget Amount *help
¥16,840,000 (Direct Cost: ¥15,100,000、Indirect Cost: ¥1,740,000)
Fiscal Year 2007: ¥7,540,000 (Direct Cost: ¥5,800,000、Indirect Cost: ¥1,740,000)
Fiscal Year 2006: ¥9,300,000 (Direct Cost: ¥9,300,000)
Keywordscalpain / enzyme / protein / proteolysis / mutant mouse / digestive tract / membrane traffiching / COPI / 蛋白分解 / 胃潰瘍 / 食品 / 粘膜
Research Abstract

Calpains are a cytosolic Ca^<2+>-regulated cysteine protease. Calpains directly interact with intracellular proteins to modify or transform functions and/or activities of their substrates, and are thus called "modulator protease". Mammals have 15 independent genes for calpains, about half of which are expressed tissue specifically. These tissue-specific calpain are expected to be involved in specific functions developed in the specific tissues, and, therefore, their physiological functions are of great interest. Two of the tissue specific calpains, nCL-2/-2' and nCL-4, are predominantly expressed in digestive tracts, especially, in the epithelial mucus secreting cells. These cells protect the stomach and intestines from acid/proteases and bacteria. Therefore, these calpains' functions are considered to be related with mucus secretion mechanisms.
To elucidate physiological functions of these calpains, we constructed nCL-2: C105S "knock in" mice, which express a protease inactive mutant of nCL-2 instead of wild type nCL-2 under endogenous expression controls. A missense mutation corresponding to the Cys105 to Ser was introduced in the mouse genomic DNA, and neomycin-resistance gene (neoR) flanked by loxP sequences was inserted in the vicinity of the C105S mutation. After homologously targeted mice were obtained, they were crossed with Cre-recombinase expressing transgenic mice to excise neoR, resulting in nCL-2: C105S knock-in mice.
Using these knock-in mice and their tissues, various biochemical, cell-biological, and molecular biological analyses have been performed. As a result, nCL-2 was shown to form not only monomer but also homo-oligomers via C2-domain like domain (domain III). This novel structure suggests unique functions for nCL-2 in digestive tracts.

Report

(3 results)
  • 2007 Annual Research Report   Final Research Report Summary
  • 2006 Annual Research Report
  • Research Products

    (19 results)

All 2008 2007 2006

All Journal Article (13 results) (of which Peer Reviewed: 4 results) Presentation (6 results)

  • [Journal Article] Muscle RING-Finger Protein MuRF1 as a Connector of Muscle Energy Metabolism and Protein Synthesis.2008

    • Author(s)
      Koyama, S.
    • Journal Title

      J.Mol.Biol. 376

      Pages: 1224-1236

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Annual Research Report 2007 Final Research Report Summary
    • 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., and Sorimachi, H. (*equally contributed first authors)
    • Journal Title

      J. Mol. Biol. 376, (peer-reviewed)

      Pages: 1224-1236

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Multiple molecular interactions implicate connectin/titin N2A region as a modulating scaffold for p94/calpain 3 activity in skeletal muscle.2008

    • Author(s)
      Hayashi, C.
    • Journal Title

      J.Biol.Chem. 283(印刷中)

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Stomach-specific calpain,nCL-2/calpain 8,is active without calpain regulatory subunit,and oligomerizes through C2-like domains.2007

    • Author(s)
      Hata, S.
    • Journal Title

      J.Biol.Chem. 282

      Pages: 27847-27856

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Annual Research Report 2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Stomach-specific calpain, nCL-2/calpain 8, is active without calpain regulatory subunit, and oligomerizes through C2-like domains.2007

    • Author(s)
      Hata, S., Doi, N., Kitamura, F., and Sorimachi, H.
    • Journal Title

      J. Biol. Chem. 282, (peer-reviewed)

      Pages: 27847-27856

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Suppression of calpain-dependent cleavage of the Cdk5 activator p35 to p25 by site-specific phosphorylation.2007

    • Author(s)
      Kamei, H. et al.
    • Journal Title

      J.Biol.Chem. 282(in press)

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Stomach-specific calpain,nCL-2,localizes in mucus cells and proteolyzes the β-subunit of coatomer complex,β-COP.2006

    • Author(s)
      Hata, S.
    • Journal Title

      J.Biol.Chem. 281

      Pages: 11214-11224

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Stomach-specific calpain, nCL-2, localizes in mucus cells and proteolyzes the β-subunit of coatomer complex, β-COP.2006

    • Author(s)
      Hata, S., Koyama, S., Kawahara, H., Doi, N., Maeda, T., Toyama-Sorimachi, N., Abe, K., Suzuki, K., and Sorimachi, H.
    • Journal Title

      J. Biol. Chem. 281, (peer-reviewed)

      Pages: 11214-11224

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Stomach-specific calpain, nCL-2, localizes in mucus cells and proteolyzes the β-subunit of coatomer complex,β-COP.2006

    • Author(s)
      Hata, S. et al.
    • Journal Title

      J.Biol.Chem. 281

      Pages: 11214-24

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Calpain system regulates the differentiation of adult primitive mesenchymal ST-13.2006

    • Author(s)
      Yajima, Y. et al.
    • Journal Title

      Endocrinology 147

      Pages: 4811-19

    • Related Report
      2006 Annual Research Report
  • [Journal Article] N2A connectin/titin suppressed disassembly of p94/CAPN3 caused by autolysis of IS2 but not IS1 in a genetic reporter system.2006

    • Author(s)
      Ono, Y.et al.
    • Journal Title

      J.Biol.Chem. 281

      Pages: 18519-31

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Crystal structure of neoculin : insights into its sweetness and taste-modifying activity.2006

    • Author(s)
      Shimizu-Ibuka, A et al.
    • Journal Title

      J.Mol.Biol. 359

      Pages: 148-158

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Nutrient-dependent multimerization of the mammalian target of rapamycin through the N-terminal HEAT repeat region.2006

    • Author(s)
      Takahara, T. et al.
    • Journal Title

      J.Biol.Chem. 281

      Pages: 28605-14

    • Related Report
      2006 Annual Research Report
  • [Presentation] Proteolytic regulation of creatine-kinase by muscle-specific RING-finger protein, MURF1.2008

    • Author(s)
      Koyama, S., Hata, S., Witt, C. C., Ono, Y., Ojima, K., Chiba, T., Doi, N., Kitamura, F., Tanaka, K., Abe, K., Witt, S., Labeit, S., and Sorimachi, H.
    • Organizer
      Nogei-kagakukai
    • Place of Presentation
      Nagoya, Japan
    • Year and Date
      2008-03-28
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Enzymatic characterization of stomach-apecific calpain, nCL-2.2007

    • Author(s)
      Hata, S., Kitamura, F., Doi, N., and Sorimachi, H.
    • Organizer
      BMB2007
    • Place of Presentation
      Yokohama, Japan
    • Year and Date
      2007-12-12
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] 胃特異的カルパインnCL-2/calpain 8aの酵素学的性質の解析2007

    • Author(s)
      秦 勝志
    • Organizer
      BMB2007
    • Place of Presentation
      横浜
    • Year and Date
      2007-12-12
    • Related Report
      2007 Annual Research Report
  • [Presentation] RING蛋白質MURF1を介した筋細胞エネルギー恒常性維持機構の解析(Possible regulation of energy metabolism by MURF1)2007

    • Author(s)
      小山傑
    • Organizer
      2007年度農芸化学会
    • Place of Presentation
      東京
    • Year and Date
      2007-03-25
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Possible regulation of energy metabolism by MURF1.2007

    • Author(s)
      Koyama, S., Hata, S., Witt, C. C., Ono, Y., Ojima, K., Chiba, T., Doi, N., Kitamura, F., Tanaka, K., Abe, K., Witt, S., Labeit, S., and Sorimach, H.
    • Organizer
      Nogei-kagakukai
    • Place of Presentation
      Tokyo, Japan
    • Year and Date
      2007-03-25
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Physiological functions of a stomach-specific calpain, nCL-2, in the mucus secreting cells.2006

    • Author(s)
      ata, S., Koyama, S., Kawahara, H., Doi, N., Maeda, T., Toyama-Sorimachi, N., Abe, K., Suzuki, K., and Sorimachi, H.
    • Organizer
      20th IUBMB International Congress of Biochemistry and Molecular Biology and 11th FAOBMB Congress.
    • Place of Presentation
      Kyoto, Japan
    • Year and Date
      2006-06-23
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary

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Published: 2006-04-01   Modified: 2016-04-21  

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