Muscle-specific RING finger-1 interacts with titin to regulate sarcomeric M-line and thick filament structure and may have nuclear functions via its interaction with glucocorticoid modulatory element binding protein-1.
Muscle-specific RING finger-1 interacts with titin to regulate sarcomeric M-line and thick filament structure and may have nuclear functions via its interaction with glucocorticoid modulatory element binding protein-1.
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DOI：
10.1083/jcb.200108089
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发表时间：
2002-04-01
期刊：
影响因子：
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通讯作者：
Gregorio CC
中科院分区：
文献类型：
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作者：
McElhinny AS;Kakinuma K;Sorimachi H;Labeit S;Gregorio CC
肌瘤蛋白Titin的COOH末端A168-170区域与肌肉特异性RING-1(MURF-1)相互作用。为了研究这种相互作用的功能意义，我们在心肌细胞中表达了编码Titin的M-line区域和MURF-1的特定片段的绿色荧光蛋白融合载体。当MURF-1或其中心区(包含其Titin结合部位)表达时，Titin的M线区域的完整性被显著破坏。Titin的M线区域的破坏也导致粗丝成分的扰动，但令人惊讶的是，Titin的NH2末端或I带区域、Z线或细丝没有扰动。这种特殊的表型也是由Titin A168-170的表达引起的。这些数据表明，Titin与MURF-1的相互作用对于肌节M线区域的稳定性是重要的。Murf-1还与泛素结合酶-9和异肽酶T-3结合，这两种酶参与泛素相关修饰物介导的小核进口，以及糖皮质激素调节元件结合蛋白-1(GMEB-1)，后者是一种转录调节因子。与我们的体外结合数据表明MURF-1具有核功能一致，内源性MURF-1也在一些心肌细胞的细胞核中被检测到。MURF-1与肌动蛋白和GMEB-1的双重相互作用可能将肌原纤维信号通路(可能包括肌动蛋白的激动域)与肌肉基因表达联系起来。
The COOH-terminal A168–170 region of the giant sarcomeric protein titin interacts with muscle-specific RING finger-1 (MURF-1). To investigate the functional significance of this interaction, we expressed green fluorescent protein fusion constructs encoding defined fragments of titin's M-line region and MURF-1 in cardiac myocytes. Upon expression of MURF-1 or its central region (containing its titin-binding site), the integrity of titin's M-line region was dramatically disrupted. Disruption of titin's M-line region also resulted in a perturbation of thick filament components, but, surprisingly, not of the NH2-terminal or I-band regions of titin, the Z-lines, or the thin filaments. This specific phenotype also was caused by the expression of titin A168–170. These data suggest that the interaction of titin with MURF-1 is important for the stability of the sarcomeric M-line region. MURF-1 also binds to ubiquitin-conjugating enzyme-9 and isopeptidase T-3, enzymes involved in small ubiquitin-related modifier–mediated nuclear import, and with glucocorticoid modulatory element binding protein-1 (GMEB-1), a transcriptional regulator. Consistent with our in vitro binding data implicating MURF-1 with nuclear functions, endogenous MURF-1 also was detected in the nuclei of some myocytes. The dual interactions of MURF-1 with titin and GMEB-1 may link myofibril signaling pathways (perhaps including titin's kinase domain) with muscle gene expression.