Biochemical Basis of Skin Disease Mal de Meleda: SLURP-1 Mutants Differently Affect Keratinocyte Proliferation and Apoptosis
Biochemical Basis of Skin Disease Mal de Meleda: SLURP-1 Mutants Differently Affect Keratinocyte Proliferation and Apoptosis
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DOI：
10.1016/j.jid.2021.01.035
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发表时间：
2021-08-19
影响因子：
6.5
通讯作者：
Lyukmanova, Ekaterina N.
中科院分区：
文献类型：
--
作者：
Shulepko, Mikhail A.;Bychkov, Maxim L.;Lyukmanova, Ekaterina N.
Mal de Meleda是一种常染色体隐性掌跖角化病，与编码SLURP-1的基因突变相关。SLURP-1通过与α 7型烟碱乙酰胆碱受体相互作用控制角质形成细胞的生长、分化和凋亡。SLURP-1具有三指结构，具有β结构核心（头部）和三个延长的环（手指）。为了确定SLURP-1突变的作用，我们产生了22种蛋白质的突变变体，包括那些参与Mal de Meleda发病机制的变体。除了R71 H、R71 P、T52 A、R96 P和L98 P之外的所有突变体都以折叠形式产生。SLURP-1减少了Het-1A角质形成细胞的生长;因此，我们研究了突变对其抗增殖活性的影响。环I和III中的突变导致蛋白失活，而环II中的大多数突变增加SLURP-1抗增殖活性。位于蛋白质头部的R96和L98残基的丙氨酸取代导致额外的促凋亡活性的出现。我们的研究结果与Mal de Meleda表型的多样性一致。使用获得的功能数据，SLURP-1/a7型烟碱乙酰胆碱受体复合物在计算机中建模。我们的研究提供了关于SLURP-1突变在Mal de Meleda发病机制中作用的功能和结构信息，并预测了可能驱动该疾病的SLURP-1变体。
Mal de Meleda is an autosomal recessive palmoplantar keratoderma associated with mutations in a gene encoding SLURP-1. SLURP-1 controls growth, differentiation, and apoptosis of keratinocytes by interaction with alpha 7-type nicotinic acetylcholine receptors. SLURP-1 has a three-finger structure with a beta-structural core (head) and three prolonged loops (fingers). To determine the role of SLURP-1 mutations, we produced 22 mutant variants of the protein, including those involved in Mal de Meleda pathogenesis. All mutants except R71H, R71P, T52A, R96P, and L98P were produced in the folded form. SLURP-1 reduces the growth of Het-1A keratinocytes; thus, we studied the influence of the mutations on its antiproliferative activity. Mutations in loops I and III led to the protein inactivation, whereas most mutations in loop II increased SLURP-1 antiproliferative activity. Alanine substitutions of R96 and L98 residues located in the protein head resulted in the appearance of additional pro-apoptotic activity. Our results agree with the diversity of Mal de Meleda phenotypes. Using obtained functional data, the SLURP-1/a7 type nicotinic acetylcholine receptor complex was modeled in silico. Our study provides functional and structural information about the role of the SLURP-1 mutations in Mal de Meleda pathogenesis and predicts SLURP-1 variants, which could drive the disease.