Maturation of the malarial phosphatidylserine decarboxylase is mediated by high affinity binding to anionic phospholipids.
Maturation of the malarial phosphatidylserine decarboxylase is mediated by high affinity binding to anionic phospholipids.
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DOI：
10.1016/j.jbc.2023.104659
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发表时间：
2023-05
影响因子：
4.8
通讯作者：
Voelker, Dennis R.
中科院分区：
文献类型：
--
作者：
Choi, Jae-Yeon;Lopes, Lauren;Ben Mamoun, Choukri;Voelker, Dennis R.
磷脂酰丝氨酸脱羧酶（PS decarboxylases，PSD）催化PS脱羧生成磷脂酰乙醇胺是大多数真核生物必需的过程。将疟疾PSD酶原加工成其活性α和β亚基是通过阴离子磷脂调节的自体内切蛋白水解机制进行的，其中PS充当激活剂，磷脂酰甘油（PG）、磷脂酰肌醇和磷脂酸充当抑制剂。这种调节的生物物理机制仍然未知。我们使用固相脂质结合，脂质体结合试验，和表面等离子体共振检查加工缺陷型疟原虫PSD（PkPSDS308A）突变酶的结合特异性，并证明PSD酶原强烈结合PS和PG，但不磷脂酰乙醇胺和磷脂酰胆碱。PkPSD与PS和PG的平衡解离常数（Kd）分别为80.4 nM和66.4 nM。PSD与PS的相互作用被钙抑制，表明结合机制涉及离子相互作用。WT PkPSD酶原的体外加工也受到钙的抑制，这与PS通过离子相互作用与PkPSD结合是酶原加工所需的结论一致。肽图谱鉴定了负责结合PS的酶原中的多元氨基酸基序。总之，这些数据表明，疟疾PSD成熟是通过PkPSD酶原和阴离子脂质之间的强物理关联来调节的。抑制酶原和脂质之间的特异性相互作用可以提供破坏PSD酶活性的新机制，PSD酶活性已被建议作为抗微生物剂和抗癌疗法的靶标。
Decarboxylation of phosphatidylserine (PS) to form phosphatidylethanolamine by PS decarboxylases (PSDs) is an essential process in most eukaryotes. Processing of a malarial PSD proenzyme into its active alpha and beta subunits is by an autoendoproteolytic mechanism regulated by anionic phospholipids, with PS serving as an activator and phosphatidylglycerol (PG), phosphatidylinositol, and phosphatidic acid acting as inhibitors. The biophysical mechanism underlying this regulation remains unknown. We used solid phase lipid binding, liposome-binding assays, and surface plasmon resonance to examine the binding specificity of a processing-deficient Plasmodium PSD (PkPSDS308A) mutant enzyme and demonstrated that the PSD proenzyme binds strongly to PS and PG but not to phosphatidylethanolamine and phosphatidylcholine. The equilibrium dissociation constants (Kd) of PkPSD with PS and PG were 80.4 nM and 66.4 nM, respectively. The interaction of PSD with PS is inhibited by calcium, suggesting that the binding mechanism involves ionic interactions. In vitro processing of WT PkPSD proenzyme was also inhibited by calcium, consistent with the conclusion that PS binding to PkPSD through ionic interactions is required for the proenzyme processing. Peptide mapping identified polybasic amino acid motifs in the proenzyme responsible for binding to PS. Altogether, the data demonstrate that malarial PSD maturation is regulated through a strong physical association between PkPSD proenzyme and anionic lipids. Inhibition of the specific interaction between the proenzyme and the lipids can provide a novel mechanism to disrupt PSD enzyme activity, which has been suggested as a target for antimicrobials, and anticancer therapies.
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影响因子：
4.8
作者：
Choi, Jae-Yeon;Augagneur, Yoann;Voelker, Dennis R.
通讯作者：
Voelker, Dennis R.
影响因子：
4.1
作者：
Kuge, O;Saito, K;Nishijima, M
通讯作者：
Nishijima, M
影响因子：
4.6
作者：
Cho G;Lee E;Kim J
通讯作者：
Kim J
影响因子：
3.6
作者：
Baunaure, F;Eldin, P;Vial, H
通讯作者：
Vial, H
影响因子：
4.8
作者：
Cho, EG;Kim, MG;Park, D
通讯作者：
Park, D