A unique leucine-valine adhesive motif supports structure and function of protein disulfide isomerase P5 via dimerization
A unique leucine-valine adhesive motif supports structure and function of protein disulfide isomerase P5 via dimerization
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DOI：
10.1016/j.str.2021.03.016
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发表时间：
2021-12-02
期刊：
影响因子：
5.7
通讯作者：
Inaba, Kenji
中科院分区：
文献类型：
--
作者：
Okumura, Masaki;Kanemura, Shingo;Inaba, Kenji
P5，也称为PDIA 6，是参与ER质量控制的PDI家族成员。在这里，我们揭示了P5通过N-末端硫氧还蛋白样结构域中包含的独特粘附基序二聚化。与传统的每两个螺旋转一个亮氨酸残基（类似于30个残基的平行α螺旋）的亮氨酸拉链基序不同，这种粘附基序包括在第三或第四位置上跨越15个残基的反平行α螺旋上的5个螺旋转的亮氨酸/缬氨酸残基的周期性重复。螺旋。P5二聚化界面通过几个相互盐桥和原聚体之间的C-封端相互作用进一步稳定。一个单体P5突变体与受损的粘附基序显示结构不稳定和局部展开，并表现为异常蛋白，诱导ER应激反应。将P5与单体结合会损害其通过分子间二硫键还原与IRE 1 α结合的能力及其在体外对伴侣蛋白功能的Ca 2+依赖性调节。因此，亮氨酸-缬氨酸粘附基序支持P5的结构和功能。
P5, also known as PDIA6, is a PDI family member involved in the ER quality control, Here, we revealed that P5 dimerizes via a unique adhesive motif contained in the N-terminal thioredoxin-like domain. Unlike conventional leucine zipper motifs with leucine residues every two helical turns on similar to 30-residue parallel alpha helices, this adhesive motif includes periodic repeats of leucine/valine residues at the third or fourth position spanning five helical turns on 15-residue anti-parallel alpha helices. The P5 dimerization interface is further stabilized by several reciprocal salt bridges and C-capping interactions between protomers. A monomeric P5 mutant with the impaired adhesive motif showed structural instability and local unfolding, and behaved as aberrant proteins that induce the ER stress response. Disassembly of P5 to monomers compromised its ability to inactivate IRE1 alpha via intermolecular disulfide bond reduction and its Ca2+-dependent regulation of chaperone function in vitro. Thus, the leucine-valine adhesive motif supports structure and function of P5.