Mutants only partially represent characteristics of calcium-release-activated calcium channel gating

被引:0
|
作者
Huo, Jun [1 ]
Lu, Ben-zhuo [2 ]
Dong, Hao [1 ,3 ,4 ,5 ]
机构
[1] Nanjing Univ, Kuang Yaming Honors Sch, Nanjing 210023, Peoples R China
[2] Chinese Acad Sci, Acad Math & Syst Sci, Univ Chinese Acad Sci, CEMS,LSEC,NCMIS,Sch Math Sci, Beijing 100190, Peoples R China
[3] Nanjing Univ, Inst Brain Sci, Nanjing 210023, Peoples R China
[4] Nanjing Univ, State Key Lab Analyt Chem Life Sci, Nanjing 210023, Peoples R China
[5] Nanjing Univ, Engn Res Ctr Prot & Peptide Med, Minist Educ, Nanjing 210023, Peoples R China
基金
中国国家自然科学基金;
关键词
Calcium-release-activated calcium channel; Gating mechanism; Molecular dynamics simulations; Mutant; Free energy profile; CRAC CHANNEL; ION SELECTIVITY; ORAI1; PERMEATION; MUTATIONS; STIM1;
D O I
10.1063/1674-0068/cjcp2111231
中图分类号
O64 [物理化学(理论化学)、化学物理学]; O56 [分子物理学、原子物理学];
学科分类号
070203 ; 070304 ; 081704 ; 1406 ;
摘要
Calcium-release-activated calcium (CARC) channels are one of the major pathways of calcium entry in non-excitable cells. Despite a decade or two of research, its regulatory mechanism is not yet thoroughly understood. The slow progress is due to the complexity of its pores (i.e., Orai) on one hand and the difficulty in capturing its regulatory complex on the other hand. As a result, possible gating mechanisms have often been speculated by exploring the structure and properties of constitutive open mutants. However, there is much debate about how they can truly reflect the gating of CRAC channels under physiological conditions. In the present study, we combined molecular dynamics simulations with free energy calculations to study three dOrai mutants (G170P, H206A, and P288A), and further calculated their current-voltage curves. Results show that these constructs adopt different approaches to maintain their conductive state. Meanwhile they have unique pore structures and distinctive rectification properties and ion selectivity for cations compared to wild-type pores. We conclude that although the mutants may partially capture the gating motion characteristics of wild-type pores, the information obtained from these mutants is likely not a true reflection of CRAC channel gating under physiological conditions.
引用
收藏
页码:915 / 924
页数:10
相关论文
共 50 条
  • [21] Gating of the calcium release-activated calcium channel: Insights from molecular simulations of the wild type and V174A mutant
    Dong, Hao
    Carnevale, Vincenzo
    Florin, Giacomo
    Klein, Michael L.
    ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2013, 246
  • [22] CHANNEL SELECTIVITY AND GATING SPECIFICITY OF CALCIUM-INDUCED CALCIUM RELEASE CHANNEL IN ISOLATED SARCOPLASMIC-RETICULUM
    NAGASAKI, K
    KASAI, M
    JOURNAL OF BIOCHEMISTRY, 1984, 96 (06): : 1769 - 1775
  • [23] Effects of calcium channel blockers on calcium release-activated calcium currents in rat hepatocytes
    Cui, GY
    Li, JM
    Cui, H
    Hao, LY
    Liu, DJ
    Zhang, KY
    ACTA PHARMACOLOGICA SINICA, 1999, 20 (05): : 415 - 418
  • [24] Calcium Ion Fluctuations Alter Channel Gating in a Stochastic Luminal Calcium Release Site Model
    Ji, Hao
    Li, Yaohang
    Weinberg, Seth H.
    BIOINFORMATICS RESEARCH AND APPLICATIONS (ISBRA 2015), 2015, 9096 : 162 - 174
  • [25] LUMENAL CALCIUM MODULATES UNITARY CONDUCTANCE AND GATING OF A PLANT VACUOLAR CALCIUM-RELEASE CHANNEL
    JOHANNES, E
    SANDERS, D
    JOURNAL OF MEMBRANE BIOLOGY, 1995, 146 (02): : 211 - 224
  • [26] Calcium Ion Fluctuations Alter Channel Gating in a Stochastic Luminal Calcium Release Site Model
    Ji, Hao
    Li, Yaohang
    Weinberg, Seth H.
    IEEE-ACM TRANSACTIONS ON COMPUTATIONAL BIOLOGY AND BIOINFORMATICS, 2017, 14 (03) : 611 - 619
  • [27] Bidirectional regulation of calcium release-activated calcium (CRAC) channel by SARAF
    Zomot, Elia
    Cohen, Hadas Achildiev
    Dagan, Inbal
    Militsin, Ruslana
    Palty, Raz
    JOURNAL OF CELL BIOLOGY, 2021, 220 (12):
  • [28] The contribution of calcium release activated calcium channel in T cell proliferation and function
    Liu, Shuang
    Nadler, Monica
    Kinet, Jean-Pierre
    JOURNAL OF PHARMACOLOGICAL SCIENCES, 2010, 112 : 216P - 216P
  • [29] Molecular mechanisms of gating in the calcium-activated chloride channel bestrophin
    Miller, Alexandria N.
    Vaisey, George
    Long, Stephen B.
    ELIFE, 2019, 8
  • [30] A unified model of presynaptic release site gating by calcium channel domains
    Gentile, L
    Stanley, EF
    EUROPEAN JOURNAL OF NEUROSCIENCE, 2005, 21 (01) : 278 - 282