Primitive Phospholamban- and Sarcolipin-like Peptides Inhibit the Sarcoplasmic Reticulum Calcium Pump SERCA.
Primitive Phospholamban- and Sarcolipin-like Peptides Inhibit the Sarcoplasmic Reticulum Calcium Pump SERCA.
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原始的磷脂和萨科脂蛋白样肽抑制肌质网钙泵Serca。
DOI：
10.1021/acs.biochem.2c00246
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发表时间：
2022-07-19
期刊：
影响因子：
2.9
通讯作者：
Young, Howard S.
中科院分区：
文献类型：
--
作者：
Bak, Jessi J.;Aguayo-Ortiz, Rodrigo;Rathod, Nishadh;Primeau, Joseph O.;Khan, Muhammad Bashir;Robia, Seth L.;Lemieux, M. Joanne;Espinoza-Fonseca, Michel L.;Young, Howard S.
细胞内钙信号对所有生命界都是必不可少的。这一过程的一个重要部分是肌质内质网Ca 2 +-ATP酶（SERCA），它维持细胞内钙稳态所需的低胞质钙水平。在高等生物中，SERCA受一系列组织特异性跨膜亚基的调节，如心肌中的受磷蛋白和骨骼肌中的肌磷脂。这些调节轴对于肌肉收缩性是如此重要，以至于SERCA、受磷蛋白和肌磷脂在哺乳动物物种中几乎是不变的。随着节肢动物sarcolambans的发现，钙泵调节亚基家族似乎跨越了从节肢动物到人类超过5.5亿年的进化分歧。这种进化上的分歧反映在肽序列上，肽序列彼此之间差异很大，只是模糊地类似于受磷蛋白和肌磷脂。sarcolambans的发现让我们解决了两个问题。在哺乳动物SERCA活性的跨膜肽调节中，允许多少序列变异？尽管序列相似性有限，趋异肽序列在其调节活性中是否模仿受磷蛋白或肌磷脂？我们表达和纯化重组sarcolamban肽从三种不同的节肢动物。将所述肽与哺乳动物SERCA 1a共重构为蛋白脂质体，并测量每种肽对表观钙亲和力和SERCA最大活性的影响。所有三种肽都是SERCA的超级抑制剂，表现出受磷蛋白样或肌磷脂样特征。分子建模、蛋白质-蛋白质对接和分子动力学模拟揭示了趋异肽的新特征及其SERCA调节特性。
Intracellular calcium signaling is essential for all kingdoms of life. An important part of this process is the sarco-endoplasmic reticulum Ca2+-ATPase (SERCA), which maintains the low cytosolic calcium levels required for intracellular calcium homeostasis. In higher organisms, SERCA is regulated by a series of tissue-specific transmembrane subunits such as phospholamban in cardiac muscles and sarcolipin in skeletal muscles. These regulatory axes are so important for muscle contractility that SERCA, phospholamban and sarcolipin, are practically invariant across mammalian species. With the recent discovery of the arthropod sarcolambans, the family of calcium pump regulatory subunits appears to span more than 550 million years of evolutionary divergence from arthropods to humans. This evolutionary divergence is reflected in the peptide sequences, which vary enormously from one another and only vaguely resemble phospholamban and sarcolipin. The discovery of the sarcolambans allowed us to address two questions. How much sequence variation is tolerated in the regulation of mammalian SERCA activity by the transmembrane peptides? Do divergent peptide sequences mimic phospholamban or sarcolipin in their regulatory activities despite limited sequence similarity? We expressed and purified recombinant sarcolamban peptides from three different arthropods. The peptides were co-reconstituted into proteoliposomes with mammalian SERCA1a and the effect of each peptide on the apparent calcium affinity and maximal activity of SERCA was measured. All three peptides were superinhibitors of SERCA, exhibiting either phospholamban-like or sarcolipin-like characteristics. Molecular modeling, protein-protein docking, and molecular dynamics simulations revealed novel features of the divergent peptides and their SERCA regulatory properties.
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