心磷脂和磷脂酰胆碱相互作用对细胞色素c构象集合的影响。,Biochemistry

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心磷脂和磷脂酰胆碱相互作用对细胞色素c构象集合的影响。
Biochemistry ( IF 2.9 ) Pub Date : 2019-08-05 00:00:00 , DOI: 10.1021/acs.biochem.9b00495
Lisa Szymkowicz ₁ , Cristina Lento ₁ , Derek J Wilson _{1,

2}

Affiliation

细胞色素c（Cyt c）主要因其在电子传输链中的功能而闻名，它通过与心磷脂（CL）的特异性相互作用，在线粒体诱导的细胞凋亡的引发中起着关键作用，而心磷脂（CL）是在线粒体内膜中发现的带负电荷的磷脂。在这项工作中，我们研究了Cyt c的构象动力学在存在CL和磷脂酰胆碱（PC）的情况下，线粒体膜中也存在磷脂，以更好地了解这些相互作用如何驱动转化为过氧化物酶活性蛋白。使用离子迁移质谱和毫秒级氢-氘交换质谱，我们证明了脂质结合的集合体中的异质性，两性离子（PC）磷脂诱导过氧化物酶配位所必需的残基不稳定，并增加了血红素结合近端表面的动力学口袋。与经典模型对CL驱动Cyt c的预期相反过氧化物酶的激活，与CL的相互作用表明可以加强血红素的配位。为了使这种观察与CL与过氧化物酶激活相关的有力支持的观点相一致，我们提出了一种机制，其中CL稳定了过氧化物酶有活性和无活性形式之间的构象转变。

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Impact of Cardiolipin and Phosphatidylcholine Interactions on the Conformational Ensemble of Cytochrome c.

Primarily known for its function in the electron transport chain, cytochrome c (Cyt c) also plays a critical role in the initiation of mitochondrially induced apoptosis through specific interactions with cardiolipin (CL), a negatively charged phospholipid found in the inner mitochondrial membrane. In this work, we study the conformational dynamics of Cyt c in the presence of CL and phosphatidylcholine (PC) phospholipids also present in the mitochondrial membrane to better understand how these interactions might drive transformation to the peroxidase-active protein. Using ion mobility mass spectrometry and millisecond hydrogen–deuterium exchange mass spectrometry, we demonstrate heterogeneity in the lipid-bound ensemble, with zwitterionic (PC) phospholipids inducing destabilization of residues necessary for peroxidase coordination, and increased dynamics on the proximal face of the heme binding pocket. In contrast to what might be expected from classical models for CL-driven Cyt c peroxidase activation, interactions with CL are shown to rigidify heme coordination. To reconcile this observation with the well-supported view that CL is linked to peroxidase activation, we propose a mechanism in which CL stabilizes the conformational transition between the peroxidase-active and inactive forms.

更新日期：2019-08-05

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