A disease-associated mutation in fibrillin-1 differentially regulates integrin-mediated cell adhesion
A disease-associated mutation in fibrillin-1 differentially regulates integrin-mediated cell adhesion
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DOI：
10.1074/jbc.ra119.011109
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发表时间：
2019-11-29
影响因子：
4.8
通讯作者：
Sundaram, Aparna B.
中科院分区：
文献类型：
--
作者：
Del Cid, Joselyn S.;Reed, Nilgun Isik;Sundaram, Aparna B.
纤维蛋白作为弹性纤维组装的支架，有助于维持组织的动态平衡，并调节细胞外空间的生长因子信号。纤维蛋白-1是一种模块化的糖蛋白，含有7种潜在的转化生长因子？(TGF？)结合类蛋白(TB)结构域，并通过整合素与其第4个TB结构域中的RGD基序结合来介导细胞黏附。TB4中的一组错义突变会导致僵硬皮肤综合征(SSS)，这是一种罕见的常染色体显性硬皮病形式。纤维化的表型被认为是由纤维蛋白-1介导整合素结合能力的变化所调节的。我们研究了每种RGD结合整合素调节细胞与纤维蛋白-1或致病变异体黏附的能力。我们的数据显示，在8个RGD结合整合素中，有7个可以介导与纤维蛋白-1的黏附。SSS的单一氨基酸替代(W1570C)显著抑制整合素5 1、V5和V6介导的黏附，部分抑制V1介导的黏附，但不抑制8 1或IIB 3介导的黏附。在SSS突变背景中，半胱氨酸残基的存在取代了高度保守的色氨酸1570，改变了同一结构域中包含暴露的RGD序列的区域的构象，从而不同地影响纤维蛋白与不同的RGD结合整合素的相互作用。
Fibrillins serve as scaffolds for the assembly of elastic fibers that contribute to the maintenance of tissue homeostasis and regulate growth factor signaling in the extracellular space. Fibrillin-1 is a modular glycoprotein that includes 7 latent transforming growth factor ? (TGF?)-binding protein-like (TB) domains and mediates cell adhesion through integrin binding to the RGD motif in its 4th TB domain. A subset of missense mutations within TB4 cause stiff skin syndrome (SSS), a rare autosomal dominant form of scleroderma. The fibrotic phenotype is thought to be regulated by changes in the ability of fibrillin-1 to mediate integrin binding. We characterized the ability of each RGD-binding integrin to mediate cell adhesion to fibrillin-1 or a disease-causing variant. Our data show that 7 of the 8 RGD-binding integrins can mediate adhesion to fibrillin-1. A single amino acid substitution responsible for SSS (W1570C) markedly inhibited adhesion mediated by integrins ?5?1, ?v?5, and ?v?6, partially inhibited adhesion mediated by ?v?1, and did not inhibit adhesion mediated by ?8?1 or ?IIb?3. Adhesion mediated by integrin ?v?3 depended on the cell surface expression level. In the SSS mutant background, the presence of a cysteine residue in place of highly conserved tryptophan 1570 alters the conformation of the region containing the exposed RGD sequence within the same domain to differentially affect fibrillin's interactions with distinct RGD-binding integrins.