본문 바로가기
HOME> 논문 > 논문 검색상세

논문 상세정보

The Journal of biological chemistry v.292 no.4, 2017년, pp.1385 - 1395   SCI SCIE
본 등재정보는 저널의 등재정보를 참고하여 보여주는 베타서비스로 정확한 논문의 등재여부는 등재기관에 확인하시기 바랍니다.

The Arrhythmogenic Calmodulin p.Phe142Leu Mutation Impairs C-domain Ca2+ Binding but Not Calmodulin-dependent Inhibition of the Cardiac Ryanodine Receptor

Søndergaard, Mads Toft (From the Department of Chemistry and Bioscience, Aalborg University, 9220 Aalborg, Denmark, ); Liu, Yingjie (the Libin Cardiovascular Institute of Alberta, the Department of Physiology and Pharmacology and the Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta T2N 1N4, Canada, ); Larsen, Kamilla Taunsig (From the Department of Chemistry and Bioscience, Aalborg University, 9220 Aalborg, Denmark, ); Nani, Alma (the Department of Molecular Biophysics and Physiology, Rush University Medical Center, Chicago, Illinois 60612 ); Tian, Xixi (the Libin Cardiovascular Institute of Alberta, the Department of Physiology and Pharmacology and the Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta T2N 1N4, Canada, ); Holt, Christian (From the Department of Chemistry and Bioscience, Aalborg University, 9220 Aalborg, Denmark, ); Wang, Ruiwu (the Libin Cardiovascular Institute of Alberta, the Department of Physiology and Pharmacology and the Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Al ); Wimmer, Reinhard ( ); Van Petegem, Filip ( ); Fill, Michael ( ); Chen, S. R. Wayne ( ); Overgaard, Michael Toft ( );
  • 초록  

    A number of point mutations in the intracellular Ca 2+ -sensing protein calmodulin (CaM) are arrhythmogenic, yet their underlying mechanisms are not clear. These mutations generally decrease Ca 2+ binding to CaM and impair inhibition of CaM-regulated Ca 2+ channels like the cardiac Ca 2+ release channel (ryanodine receptor, RyR2), and it appears that attenuated CaM Ca 2+ binding correlates with impaired CaM-dependent RyR2 inhibition. Here, we investigated the RyR2 inhibitory action of the CaM p.Phe142Leu mutation (F142L; numbered including the start-Met), which markedly reduces CaM Ca 2+ binding. Surprisingly, CaM-F142L had little to no aberrant effect on RyR2-mediated store overload-induced Ca 2+ release in HEK293 cells compared with CaM-WT. Furthermore, CaM-F142L enhanced CaM-dependent RyR2 inhibition at the single channel level compared with CaM-WT. This is in stark contrast to the actions of arrhythmogenic CaM mutations N54I, D96V, N98S, and D130G, which all diminish CaM-dependent RyR2 inhibition. Thermodynamic analysis showed that apoCaM-F142L converts an endothermal interaction between CaM and the CaM-binding domain (CaMBD) of RyR2 into an exothermal one. Moreover, NMR spectra revealed that the CaM-F142L-CaMBD interaction is structurally different from that of CaM-WT at low Ca 2+ . These data indicate a distinct interaction between CaM-F142L and the RyR2 CaMBD, which may explain the stronger CaM-dependent RyR2 inhibition by CaM-F142L, despite its reduced Ca 2+ binding. Collectively, these results add to our understanding of CaM-dependent regulation of RyR2 as well as the mechanistic effects of arrhythmogenic CaM mutations. The unique properties of the CaM-F142L mutation may provide novel clues on how to suppress excessive RyR2 Ca 2+ release by manipulating the CaM-RyR2 interaction.


  • 주제어

    calcium intracellular release .   calcium-binding protein .   calmodulin (CaM) .   protein-protein interaction .   ryanodine receptor .   CaM-F142L .   arrhythmia .   cardiac ryanodine receptor.  

 활용도 분석

  • 상세보기

    amChart 영역
  • 원문보기

    amChart 영역

원문보기

무료다운로드
  • 원문이 없습니다.
유료다운로드

유료 다운로드의 경우 해당 사이트의 정책에 따라 신규 회원가입, 로그인, 유료 구매 등이 필요할 수 있습니다. 해당 사이트에서 발생하는 귀하의 모든 정보활동은 NDSL의 서비스 정책과 무관합니다.

원문복사신청을 하시면, 일부 해외 인쇄학술지의 경우 외국학술지지원센터(FRIC)에서
무료 원문복사 서비스를 제공합니다.

NDSL에서는 해당 원문을 복사서비스하고 있습니다. 위의 원문복사신청 또는 장바구니 담기를 통하여 원문복사서비스 이용이 가능합니다.

이 논문과 함께 출판된 논문 + 더보기