The endoplasmic reticulum HSP40 co-chaperone ERdj3/DNAJB11 assembles and functions as a tetramer
The endoplasmic reticulum HSP40 co-chaperone ERdj3/DNAJB11 assembles and functions as a tetramer
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DOI：
10.15252/embj.201695616
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发表时间：
2017-08-01
期刊：
影响因子：
11.4
通讯作者：
Wiseman, R. Luke
中科院分区：
文献类型：
--
作者：
Chen, Kai-Chun;Qu, Song;Wiseman, R. Luke
ERdj3/DNAJB11是一种靶向内质网（ER）的HSP40共伴侣，在协调内质网和细胞外蛋白酶平衡中发挥多方面的功能。在这里，我们发现ERdj3组装成一个天然的四聚体，与其他HSP40共伴侣所观察到的二聚体结构不同。全长ERdj3的电镜结构模型表明，这些四聚体是由ERdj3结构域II和结构域III不同的亚基间相互作用形成的二聚体的二聚体。II结构域内175-190残基的靶向删除使ERdj3成为一种稳定的二聚体，可以折叠并有效地从哺乳动物细胞中分泌。这种二聚体ERdj3在内质网和细胞外环境中都显示出底物结合受损，并且与内质网HSP70伴侣BiP的相互作用减少。此外，我们发现二聚体ERdj3的过表达加剧了内质网应激依赖性的不稳定、易聚集蛋白分泌减少，并增加了其在细胞外环境中作为可溶性低聚物的积累。这些结果表明，ERdj3四聚化是ERdj3在内质网应激和无内质网应激下参与协调内质网和细胞外蛋白酶平衡的重要结构框架。
ERdj3/DNAJB11 is an endoplasmic reticulum (ER)-targeted HSP40 co-chaperone that performs multifaceted functions involved in coordinating ER and extracellular proteostasis. Here, we show that ERdj3 assembles into a native tetramer that is distinct from the dimeric structure observed for other HSP40 co-chaperones. An electron microscopy structural model of full-length ERdj3 shows that these tetramers are arranged as a dimer of dimers formed by distinct inter-subunit interactions involving ERdj3 domain II and domain III. Targeted deletion of residues 175-190 within domain II renders ERdj3 a stable dimer that is folded and efficiently secreted from mammalian cells. This dimeric ERdj3 shows impaired substrate binding both in the ER and extracellular environments and reduced interactions with the ER HSP70 chaperone BiP. Furthermore, we show that overexpression of dimeric ERdj3 exacerbates ER stress-dependent reductions in the secretion of a destabilized, aggregation-prone protein and increases its accumulation as soluble oligomers in extracellular environments. These results reveal ERdj3 tetramerization as an important structural framework for ERdj3 functions involved in coordinating ER and extracellular proteostasis in the presence and absence of ER stress.