Cardiac muscle cell cytoskeletal protein 4.1: Analysis of transcripts and subcellular location-relevance to membrane integrity, microstructure, and possible role in heart failure
Cardiac muscle cell cytoskeletal protein 4.1: Analysis of transcripts and subcellular location-relevance to membrane integrity, microstructure, and possible role in heart failure
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DOI：
10.1007/s00335-004-2436-7
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发表时间：
2005-03-01
期刊：
影响因子：
2.5
通讯作者：
Pinder, JC
中科院分区：
文献类型：
--
作者：
Taylor-Harris, PM;Keating, LA;Pinder, JC
基于血影蛋白的细胞骨架组装已成为心脏功能的主要参与者;然而，心脏蛋白4.1，一个关键成分，是未表征的。蛋白质4.1进化以保护细胞膜免受机械应力并组织膜微结构。4.1蛋白质是多功能的，并且在其他活动中，将质膜和内膜上的整合/信号蛋白与基于血影蛋白的细胞骨架连接。EPB 41、EPB 41 L1、EPB 41 L2和EPB 41 L3四个基因分别编码蛋白4.1R、4.1N、4.1G和4.1B。所有这些都是广泛拼接的。根据组织和发育状态表达不同的同种型，通过包含/排除相互作用结构域来控制个体功能。我们已经定义了小鼠和人类心脏4.1转录本;除了人类中的4.1B，所有基因都显示出活性。心脏转录组成包括保守的FERM和C-末端结构域;两者都与膜结合的信号/运输/细胞粘附分子相互作用。可变剪接内和邻近的中央血影蛋白/肌动蛋白结合域，使调节细胞因子结合活性。一个新的心脏特异性外显子存在于人4.1G中，但不在小鼠中。免疫荧光显示小鼠心肌细胞内的4.1染色，因此，无论是在质膜和，交叉与肌节肌球蛋白，跨肌原纤维在靠近肌浆网的区域。这些都是血影蛋白所在的区域。4.1R在人心脏中显示类似的分布，但是存在有限的质膜染色。我们的结论是，心脏4.1s在他们的能力，交联血浆/积分细胞膜与血影蛋白肌动蛋白细胞骨架高度调节。我们推测，在心肌收缩和舒张的重复周期中，4.1s可能定位、支持和协调关键膜结合大分子组装体的功能。
The spectrin-based cytoskeleton assembly has emerged as a major player in heart functioning; however, cardiac protein 4.1, a key constituent, is uncharacterized. Protein 4.1 evolved to protect cell membranes against mechanical stresses and to organize membrane microstructure. 4.1 Proteins are multifunctional and, among other activities, link integral/signaling proteins on the plasma and internal membranes with the spectrin-based cytoskeleton. Four genes, EPB41, EPB41L1, EPB41L2, and EPB41L3 encode proteins 4.1R, 4.1N, 4.1G, and 4.1B, respectively. All are extensively spliced. Different isoforms are expressed according to tissue and developmental state, individual function being controlled through inclusion/exclusion of interactive domains. We have defined mouse and human cardiac 4.1 transcripts; other than 4.1B in humans, all genes show activity. Cardiac transcripts constitutively include conserved FERM and C-terminal domains; both interact with membrane-bound signaling/transport/cell adhesion molecules. Variable splicing within and adjacent to the central spectrin/actin-binding domain enables regulation of cytoskeleton-binding activity. A novel heart-specific exon occurs in human 4.1 G, but not in mouse. Immunofluorescence reveals 4.1 staining within mouse cardiomyocytes; thus, both at the plasma membrane and, interdigitated with sarcomeric myosin, across myofibrils in regions close to the sarcoplasmic reticulum. These are all regions to which spectrin locates. 4.1R in human heart shows similar distribution; however, there is limited plasma membrane staining. We conclude that cardiac 4.1s are highly regulated in their ability to crosslink plasma/integral cell membranes with the spectrin-actin cytoskeleton. We speculate that over the repetitive cycles of heart muscle contraction and relaxation, 4.1s are likely to locate, support, and coordinate functioning of key membrane-bound macromolecular assemblies.