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The binding of the RyR2 calcium channel to its gating protein FKBP12.6 is oppositely affected by ARVD2 and VTSIP mutations
被引:41
作者:
Tiso, N
[1
]
Salamon, M
[1
]
Bagattin, A
[1
]
Danieli, GA
[1
]
Argenton, F
[1
]
Bortolussi, M
[1
]
机构:
[1] Univ Padua, Dept Biol, I-35131 Padua, Italy
关键词:
ARVD2;
VTSIP;
cardiac;
mutation;
RyR2;
channel;
FKBP12.6;
FK506;
RyR1;
yeast;
D O I:
10.1016/S0006-291X(02)02689-X
中图分类号:
Q5 [生物化学];
Q7 [分子生物学];
学科分类号:
071010 ;
081704 ;
摘要:
Arrhythmogenic right ventricular dysplasia/cardiomyopathy type 2 (ARVD2, OMIM 600996) and stress-induced polymorphic ventricular tachycardia (VTSIP, OMIM 604772) are two cardiac diseases causing juvenile sudden death, both associated with mutations in the RyR2 calcium channel. By using a quantitative yeast two-hybrid system, we show that VTSIP- and ARVD2-associated point mutations influence positively and negatively, respectively, the binding of RyR2 to its gating protein FKBP12.6. These findings suggest that ARVD2 mutations increase RyR2-mediated calcium release to cytoplasm, while VTSIP mutations do not affect significantly cytosolic calcium levels, thereby explaining the clinical differences between the two diseases. The present two-hybrid system appears to be an efficient molecular tool to assay the binding of FKBP12s proteins to both cardiac RyR2 and skeletal muscle RyR1 isoforms, circumventing the full-length expression of this class of giant channels. We also provide evidence of the suitability of this system to test new drugs that target RyRs-FKBP12s interactions and do not affect yeast growth. (C) 2002 Elsevier Science (USA). All rights reserved.
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页码:594 / 598
页数:5
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