Control of AMP deaminase 1 binding to myosin heavy chain.
Control of AMP deaminase 1 binding to myosin heavy chain.
复制标题
DOI：
10.1152/ajpcell.1998.275.3.c870
复制
发表时间：
1998-09
期刊：
影响因子：
--
通讯作者：
I. Hisatome;T. Morisaki;H. Kamma;T. Sugama;H. Morisaki;A. Ohtahara;E. Holmes
中科院分区：
文献类型：
--
作者：
I. Hisatome;T. Morisaki;H. Kamma;T. Sugama;H. Morisaki;A. Ohtahara;E. Holmes
AMPD在维持运动后心肌细胞的腺苷酸能荷和产生肌肉中柠檬酸循环的中间产物方面起着核心作用。先前的研究表明，AMPD1在体外与肌球蛋白重链(MHC)结合；在体内，AMPD1与肌原纤维的结合随着肌肉收缩状态的不同而不同，而AMPD1与MHC的结合是激活肌细胞中该酶所必需的。本研究使用共转染模型确定了AMPD1中影响该酶与MHC结合的三个结构域，该模型允许评估引入AMPD1肽的突变。一个包含727个氨基酸残基178-333残基的结构域是AMPD1与MHC结合所必需的。AMPD1的这个区域与另一种MHC结合蛋白Titin的几个区域有序列相似性。另外两个结构域调节这种多肽与MHC的结合，以响应细胞内和细胞外的信号。位于残基660-674的核苷酸结合位点控制AMPD1与MHC的结合，以响应细胞内ATP浓度的变化。缺失分析表明，AMPD1的氨基末端65个残基在调节对ATP诱导的MHC结合抑制的敏感性中起着关键作用。AMPD1基因产物的选择性剪接改变了8-12残基的序列，产生了两种在ATP存在下表现出不同MHC结合特性的AMPD1亚型。这些发现是在提出的AMPD在心肌细胞能量产生中的不同作用的背景下讨论的。
AMP deaminase (AMPD) plays a central role in preserving the adenylate energy charge in myocytes following exercise and in producing intermediates for the citric acid cycle in muscle. Prior studies have demonstrated that AMPD1 binds to myosin heavy chain (MHC) in vitro; binding to the myofibril varies with the state of muscle contraction in vivo, and binding of AMPD1 to MHC is required for activation of this enzyme in myocytes. The present study has identified three domains in AMPD1 that influence binding of this enzyme to MHC using a cotransfection model that permits assessment of mutations introduced into the AMPD1 peptide. One domain that encompasses residues 178-333 of this 727-amino acid peptide is essential for binding of AMPD1 to MHC. This region of AMPD1 shares sequence similarity with several regions of titin, another MHC binding protein. Two additional domains regulate binding of this peptide to MHC in response to intracellular and extracellular signals. A nucleotide binding site, which is located at residues 660-674, controls binding of AMPD1 to MHC in response to changes in intracellular ATP concentration. Deletion analyses demonstrate that the amino-terminal 65 residues of AMPD1 play a critical role in modulating the sensitivity to ATP-induced inhibition of MHC binding. Alternative splicing of the AMPD1 gene product, which alters the sequence of residues 8-12, produces two AMPD1 isoforms that exhibit different MHC binding properties in the presence of ATP. These findings are discussed in the context of the various roles proposed for AMPD in energy production in the myocyte.