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首页> 外文期刊>Cell Research >The transmembrane domain of TACE regulates protein ectodomain shedding
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The transmembrane domain of TACE regulates protein ectodomain shedding

机译：TACE的跨膜结构域调节蛋白质胞外域脱落

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摘要

Numerous membrane proteins are cleaved by tumor necrosis factor-α converting enzyme (TACE), which causes the release of their ectodomains. An ADAM (a disintegrin and metalloprotease domain) family member, TACE contains several noncatalytic domains whose roles in ectodomain shedding have yet to be fully resolved. Here, we have explored the function of the transmembrane domain (TM) of TACE by coupling molecular engineering and functional analysis. A TM-free TACE construct that is anchored to the plasma membrane by a glycosylphosphatidylino-sitol (GPI)-binding polypeptide failed to restore shedding of transforming growth factor-α (TGF-α), tumor necrosis factor-α (TNF-α) and L-selectin in cells lacking endogenous TACE activity. Substitution of the TACE TM with that of the prolactin receptor or platelet-derived growth factor receptor (PDGFR) also resulted in severe loss of TGF-α shedding, but had no effects on the cleavage of TNF-α and L-selectin. Replacement of the TM in TGF-α with that of L-selectin enabled TGF-α shedding by the TACE mutants carrying the TM of prolactin receptor and PDGFR. Taken together, our observations suggest that anchorage of TACE to the lipid bilayer through a TM is required for efficient cleavage of a broad spectrum of substrates, and that the amino-acid sequence of TACE TM may play a role in regulatory specificity among TACE substrates.
机译：多种膜蛋白被肿瘤坏死因子-α转化酶（TACE）裂解，导致其胞外域释放。 TACE是ADAM（整合素和金属蛋白酶结构域）家族的成员，包含几个非催化结构域，其在胞外域脱落中的作用尚未完全解决。在这里，我们已经通过结合分子工程和功能分析探索了TACE的跨膜结构域（TM）的功能。通过糖基磷脂酰肌醇（GPI）结合多肽锚定在质膜上的无TM TACE构建体无法恢复转化生长因子-α（TGF-α），肿瘤坏死因子-α（TNF-α）的脱落缺乏内源性TACE活性的细胞中的L-选择素。用催乳素受体或血小板衍生的生长因子受体（PDGFR）替代TACE TM也会导致TGF-α脱落的严重丧失，但对TNF-α和L-选择素的裂解没有影响。用L-选择蛋白替代TGF-α中的TM，可以通过携带催乳素受体和PDGFR TM的TACE突变体使TGF-α脱落。综上所述，我们的观察结果表明，通过TTM将TACE锚定在脂质双层上是有效切割宽范围的底物所必需的，并且TACE TM的氨基酸序列可能在TACE底物之间的调节特异性中起作用。

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