ZASP interacts with the mechanosensing protein Ankrd2 and p53 in the signalling network of striated muscle.
ZASP interacts with the mechanosensing protein Ankrd2 and p53 in the signalling network of striated muscle.
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DOI：
10.1371/journal.pone.0092259
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Faulkner G
中科院分区：
文献类型：
--
作者：
Martinelli VC;Kyle WB;Kojic S;Vitulo N;Li Z;Belgrano A;Maiuri P;Banks L;Vatta M;Valle G;Faulkner G
ZASP 是一种细胞骨架 PDZ-LIM 蛋白，主要在横纹肌中表达。它形成多蛋白复合物，并在肌节的结构完整性中发挥关键作用。 ZASP 蛋白突变与肌原纤维肌病、左心室致密化不全和扩张型心肌病相关。其小鼠同源物 Cypher 的消融会导致新生儿死亡。 ZASP 有几种选择性剪接异构体，在本文中，我们阐明了其人类异构体的命名法以及它们在横纹肌中的动态和表达模式。 ZASP 和两个新的结合伙伴之间的相互作用得到了证明，这两个结合伙伴都在信号传导、基因表达调节和肌肉分化中发挥作用；机械传感蛋白 Ankrd2 和肿瘤抑制蛋白 p53。这些蛋白质和 ZASP 形成三重复合物，似乎促进了 p53 的多聚 SUMO 化。我们还展示了其两个功能域（ZM 基序和 PDZ 域）的重要性。 PDZ 结构域可以直接结合 Ankrd2 和 p53，这表明它和 p53 之间不存在对 Ankrd2 上相同结合位点的竞争。然而，p53 和缺乏 PDZ 结构域但包含 ZM 基序的 ZASP 蛋白区域之间存在对该结合位点的竞争。在 p53 响应启动子 MDM2 和 BAX 的反式激活实验中，ZASP 是 p53 的负调节因子。 ZASP ZM 基序的突变会引起蛋白质周转的改变。事实上，两个突变体 A165V 和 A171T 无法结合 Ankrd2，并且与 α-辅肌动蛋白2 的结合也很弱。这一点很重要，因为 A165V 突变导致 zaspopathy，一种特征明确的常染色体显性远端肌病。尽管该突变体引起疾病的机制仍不清楚，但这是 ZASP 疾病相关突变蛋白与野生型 ZASP 蛋白有何不同的第一个迹象。
ZASP is a cytoskeletal PDZ-LIM protein predominantly expressed in striated muscle. It forms multiprotein complexes and plays a pivotal role in the structural integrity of sarcomeres. Mutations in the ZASP protein are associated with myofibrillar myopathy, left ventricular non-compaction and dilated cardiomyopathy. The ablation of its murine homologue Cypher results in neonatal lethality. ZASP has several alternatively spliced isoforms, in this paper we clarify the nomenclature of its human isoforms as well as their dynamics and expression pattern in striated muscle. Interaction is demonstrated between ZASP and two new binding partners both of which have roles in signalling, regulation of gene expression and muscle differentiation; the mechanosensing protein Ankrd2 and the tumour suppressor protein p53. These proteins and ZASP form a triple complex that appears to facilitate poly-SUMOylation of p53. We also show the importance of two of its functional domains, the ZM-motif and the PDZ domain. The PDZ domain can bind directly to both Ankrd2 and p53 indicating that there is no competition between it and p53 for the same binding site on Ankrd2. However there is competition for this binding site between p53 and a region of the ZASP protein lacking the PDZ domain, but containing the ZM-motif. ZASP is negative regulator of p53 in transactivation experiments with the p53-responsive promoters, MDM2 and BAX. Mutations in the ZASP ZM-motif induce modification in protein turnover. In fact, two mutants, A165V and A171T, were not able to bind Ankrd2 and bound only poorly to alpha-actinin2. This is important since the A165V mutation is responsible for zaspopathy, a well characterized autosomal dominant distal myopathy. Although the mechanism by which this mutant causes disease is still unknown, this is the first indication of how a ZASP disease associated mutant protein differs from that of the wild type ZASP protein.
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