Differential lipid binding of vinculin isoforms promotes quasi-equivalent dimerization
Differential lipid binding of vinculin isoforms promotes quasi-equivalent dimerization
复制标题
DOI：
10.1073/pnas.1600702113
复制
发表时间：
2016-08-23
影响因子：
11.1
通讯作者：
Izard, Tina
中科院分区：
文献类型：
--
作者：
Chinthalapudi, Krishna;Rangarajan, Erumbi S.;Izard, Tina
全球死亡的主要原因仍然是衰弱性心脏病，例如扩张型心肌病（DCM）和肥厚型心肌病（HCM），这些疾病通常是由于粘附复合物特定成分的突变造成的。纽蛋白调节这些复合物，并在闰盘中发挥重要作用，闰盘是肌肉细胞功能和协调运动以及心脏发育和功能所必需的。携带纽蛋白家族性或散发性突变的人类患有慢性、进行性衰弱的 DCM，最终导致心力衰竭和死亡，而纽蛋白的常染色体显性突变也可能引发 HCM，导致急性心力衰竭。纽蛋白的 DCM/HCM 相关突变体出现在肌肉特异性、选择性剪接的纽蛋白亚型所特有的 68 个残基插入物中，称为美纽蛋白 (MV)。与表明 4,5-二磷酸磷酸肌醇 (PIP2) 仅诱导不对称的纽蛋白同型二聚体的研究相反，我们表明，与涉及 R975 的纽蛋白相比，磷脂结合通过准等效界面产生结构域交换的对称 MV 二聚体。尽管保留了两个 PIP2 结合位点之一，但桥接两个 PIP2 分子的对称 MV 二聚体不同于仅桥接一个 PIP2 的不对称纽蛋白二聚体。与纽蛋白不同，野生型 MV 和 DCM/HCM 相关的 R975W 突变体以非活性构象结合 PIP2，并且 R975W MV 无法二聚化。将选择性纽蛋白残基突变为其相应的 MV 残基，或反之亦然，可切换异构体的二聚体星座和脂质结合位点。总的来说，我们的数据表明 MV 同二聚化调节肌肉粘附部位的微丝附着，并进一步加深我们对 MV 介导的心脏重塑的理解。
The main cause of death globally remains debilitating heart conditions, such as dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM), which are often due to mutations of specific components of adhesion complexes. Vinculin regulates these complexes and plays essential roles in intercalated discs that are necessary for muscle cell function and coordinated movement and in the development and function of the heart. Humans bearing familial or sporadic mutations in vinculin suffer from chronic, progressively debilitating DCM that ultimately leads to cardiac failure and death, whereas autosomal dominant mutations in vinculin can also provoke HCM, causing acute cardiac failure. The DCM/HCM-associated mutants of vinculin occur in the 68-residue insert unique to the muscle-specific, alternatively spliced isoform of vinculin, termed metavinculin (MV). Contrary to studies that suggested that phosphoinositol-4,5-bisphosphate (PIP2) only induces vinculin homodimers, which are asymmetric, we show that phospholipid binding results in a domain-swapped symmetric MV dimer via a quasi-equivalent interface compared with vinculin involving R975. Although one of the two PIP2 binding sites is preserved, the symmetric MV dimer that bridges two PIP2 molecules differs from the asymmetric vinculin dimer that bridges only one PIP2. Unlike vinculin, wild-type MV and the DCM/HCM-associated R975W mutant bind PIP2 in their inactive conformations, and R975W MV fails to dimerize. Mutating selective vinculin residues to their corresponding MV residues, or vice versa, switches the isoform's dimeric constellation and lipid binding site. Collectively, our data suggest that MV homodimerization modulates microfilament attachment at muscular adhesion sites and furthers our understanding of MV-mediated cardiac remodeling.