Tejero Jesús, Kapralov Alexandr A, Baumgartner Matthew P, Sparacino-Watkins Courtney E, Anthonymutu Tamil S, Vlasova Irina I, Camacho Carlos J, Gladwin Mark T, Bayir Hülya, Kagan Valerian E
Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA; Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15219, USA; Center for Free Radical and Antioxidant Health and Center for Medical Countermeasures against Radiation, University of Pittsburgh, Pittsburgh, PA 15219, USA.
Biochim Biophys Acta. 2016 May;1861(5):391-401. doi: 10.1016/j.bbalip.2016.02.022. Epub 2016 Feb 27.
Cytoglobin (Cygb) is a hexa-coordinated hemoprotein with yet to be defined physiological functions. The iron coordination and spin state of the Cygb heme group are sensitive to oxidation of two cysteine residues (Cys38/Cys83) and/or the binding of free fatty acids. However, the roles of redox vs lipid regulators of Cygb's structural rearrangements in the context of the protein peroxidase competence are not known. Searching for physiologically relevant lipid regulators of Cygb, here we report that anionic phospholipids, particularly phosphatidylinositolphosphates, affect structural organization of the protein and modulate its iron state and peroxidase activity both conjointly and/or independently of cysteine oxidation. Thus, different anionic lipids can operate in cysteine-dependent and cysteine-independent ways as inducers of the peroxidase activity. We establish that Cygb's peroxidase activity can be utilized for the catalysis of peroxidation of anionic phospholipids (including phosphatidylinositolphosphates) yielding mono-oxygenated molecular species. Combined with the computational simulations we propose a bipartite lipid binding model that rationalizes the modes of interactions with phospholipids, the effects on structural re-arrangements and the peroxidase activity of the hemoprotein.
细胞珠蛋白（Cygb）是一种六配位血红素蛋白，其生理功能尚待确定。Cygb血红素基团的铁配位和自旋状态对两个半胱氨酸残基（Cys38/Cys83）的氧化和/或游离脂肪酸的结合敏感。然而，在蛋白质过氧化物酶活性的背景下，氧化还原与脂质调节剂在Cygb结构重排中的作用尚不清楚。为了寻找与Cygb生理相关的脂质调节剂，我们在此报告，阴离子磷脂，特别是磷脂酰肌醇磷酸酯，会影响该蛋白质的结构组织，并联合和/或独立于半胱氨酸氧化来调节其铁状态和过氧化物酶活性。因此，不同的阴离子脂质可以以半胱氨酸依赖性和半胱氨酸非依赖性方式作为过氧化物酶活性的诱导剂发挥作用。我们确定Cygb的过氧化物酶活性可用于催化阴离子磷脂（包括磷脂酰肌醇磷酸酯）的过氧化反应，产生单加氧分子物种。结合计算模拟，我们提出了一个二元脂质结合模型，该模型解释了与磷脂的相互作用模式、对结构重排的影响以及血红素蛋白的过氧化物酶活性。
