FKBP12 binding modulates ryanodine receptor channel gating
FKBP12 binding modulates ryanodine receptor channel gating
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DOI：
10.1074/jbc.m100856200
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发表时间：
2001-05-18
影响因子：
4.8
通讯作者：
Marks, AR
中科院分区：
文献类型：
--
作者：
Gaburjakova, M;Gaburjakova, J;Marks, AR
骨骼肌肌浆网上的ryanodine受体(RyR1)/钙释放通道由4个56.5万道尔顿的RyR1组成，每个RyR1结合1个FK506结合蛋白（FKBP12）， RyR1是骨骼肌兴奋-收缩耦合所必需的。FKBP12是一种顺式-反式肽基-脯氨酸异构酶，是RyR1通道正常门控所必需的。在没有FKBP12的情况下，RyR1通道表现出增加的门控频率，这表明FKBP12“稳定”了通道在打开和关闭状态。我们现在表明，将RyR1中的Val（2461）替换为Gly、Glu或Ile可阻止FKBP12与RyR1结合，从而导致通道的门控频率增加。对于V2461I突变体RyR1，通过添加FKBP12的同工异构体FKBP12.6，可以恢复正常的通道功能。这些数据确定了Val（2461）是FKBP12结合RyR1所需的关键残基，并证明了FKBP12在RyR1通道复合物中的功能作用。
The ryanodine receptor (RyR1)/calcium release channel on the sarcoplasmic reticulum of skeletal muscle is comprised of four 565,000-dalton RyR1s, each of which binds one FK506 binding protein (FKBP12), RyR1 is required for excitation-contraction coupling in skeletal muscle. FKBP12, a cis-trans peptidyl-prolyl isomerase, is required for the normal gating of the RyR1 channel. In the absence of FKBP12, RyR1 channels Exhibit increased gating frequency, suggesting that FKBP12 "stabilizes" the channel in the open and closed states. We now show that substitution of a Gly, Glu, or Ile for Val(2461) in RyR1 prevents FKBP12 binding to RyR1, resulting in channels with increased gating frequency. In the case of the V2461I mutant RyR1, normal channel function can be restored by adding FKBP12.6, an isoform of FKBP12. These data identify Val(2461) ag a critical residue required for FKBP12 binding to RyR1 and demonstrate the functional role for FKBP12 in the RyR1 channel complex.