Cross R A, Stewart M, Kendrick-Jones J
MRC Laboratory of Molecular Biology, Cambridge, England.
FEBS Lett. 1990 Mar 12;262(1):87-92. doi: 10.1016/0014-5793(90)80160-k.
The amino acid sequence of dystrophin indicates that the molecule has globular N- and C-terminal domains separated by a long central rod domain. The central rod contains multiple repeats, about 100 amino acids long and of variable length. These diverge sufficiently in sequence that, in previous studies, only 14 of the most similar repeats have been aligned and analysed in any detail. We show here that a heptad pattern of hydrophobic residues is preserved across all repeats. Using the heptad pattern together with a consensus sequence template, we identified and aligned 25 repeats in the dystrophin rod sequence. Each repeat consists of a constant-length core helix of 54 residues, coupled via a short linker to a weakly conserved variable-length helix, and then via a second linker to the next core. The variable-length helix appears truncated in repeats 10 and 13 and extended in repeats 4 and 20. The extension of repeat 20 is particularly interesting since it corresponds to a hotspot of dystrophy-inducing mutations. Detailed modelling suggests that the classical Speicher-Marchesi [(1984) Nature 311, 177-180] model for spectrin may not be appropriate to dystrophin without some modification. We propose that whilst the repeating structural motif in dystrophin is probably a bead of triple coiled coil, this bead is twice as massive as, and out of phase with, those proposed for spectrin. Our model raises the possibility that the rod domain of dystrophin may confer elasticity on the molecule. Deletions which truncate this region would then reduce the extensibility of the molecule without affecting actin crosslinking, consistent with their typically producing the relatively benign Becker phenotype of muscular dystrophy.
肌营养不良蛋白的氨基酸序列表明，该分子具有球状的N端和C端结构域，中间由一个长的中央杆状结构域隔开。中央杆包含多个重复序列，每个重复序列约100个氨基酸长，长度可变。这些重复序列在序列上差异足够大，以至于在先前的研究中，只有14个最相似的重复序列被详细比对和分析过。我们在此表明，疏水残基的七肽模式在所有重复序列中都得以保留。利用七肽模式和一个共有序列模板，我们在肌营养不良蛋白杆状序列中鉴定并比对了25个重复序列。每个重复序列由一个54个残基的恒定长度的核心螺旋组成，通过一个短连接子与一个弱保守的可变长度螺旋相连，然后通过第二个连接子与下一个核心相连。可变长度螺旋在重复序列10和13中似乎被截断，而在重复序列4和20中则有所延长。重复序列20的延长特别有趣，因为它对应于导致肌营养不良的突变热点。详细的模型分析表明，经典的血影蛋白Speicher-Marchesi [(1984)《自然》311, 177 - 180]模型可能需要经过一些修改才适用于肌营养不良蛋白。我们提出，虽然肌营养不良蛋白中的重复结构基序可能是一个三股螺旋卷曲的珠状结构，但这个珠状结构的质量是血影蛋白中所提出的珠状结构的两倍，且相位不同。我们的模型提出了一种可能性，即肌营养不良蛋白的杆状结构域可能赋予分子弹性。截断该区域的缺失会降低分子的可伸展性，而不影响肌动蛋白交联，这与它们通常产生相对良性的贝克型肌营养不良表型是一致的。
