The STI and UBA Domains of UBQLN1 Are Critical Determinants of Substrate Interaction and Proteostasis.
The STI and UBA Domains of UBQLN1 Are Critical Determinants of Substrate Interaction and Proteostasis.
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DOI：
10.1002/jcb.25880
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发表时间：
2017-08
影响因子：
4
通讯作者：
Beverly LJ
中科院分区：
文献类型：
--
作者：
Kurlawala Z;Shah PP;Shah C;Beverly LJ
Ubiquilin蛋白有5个（UBQLN 1 -4，UBQLN-L），它们在进化上是保守的，结构上是相似的。UBQLN蛋白具有3个功能结构域：N端泛素样结构域（UBL）、C端泛素相关结构域（乌巴）和中间的STI分子伴侣样区域。UBQLN 1基因的改变已经在从阿尔茨海默病到癌症的各种疾病中被检测到。UBQLN 1已在蛋白质质量控制的背景下在神经退行性疾病中进行了大量研究。一些研究假设UBQLN 1的乌巴结构域与底物的多聚泛素链结合，并通过其UBL结构域将其穿梭至蛋白酶体进行降解。UBQLN 1促进降解（Ataxin 3，EPS 15）或稳定（PSEN 1/2，BCLb）它结合的底物。决定这种命运的信号是未知的，并且存在相互矛盾的数据来支持UBQLN 1的现有工作模型。使用BCLb作为模型底物，我们表征了UBQLN 1-底物相互作用。我们确定了UBQLN 1的前两个STI结构域对于结合BCLb至关重要。UBQLN 1与BCLb的相互作用不依赖于BCLb的泛素化，但通过乌巴结构域与泛素的相互作用是其稳定所必需的。同样，我们发现UBQLN 1通过STI结构域与IGF 1 R和ESYT 2相互作用，并通过其乌巴结构域稳定这些蛋白质。不依赖于STI结构域的相互作用，例如UBL介导的与PSMD 4和BAG 6的相互作用，似乎不被UBQLN 1稳定。我们的结论是，命运的底物，UBQLN 1协会，是相互作用域特异性。
There are 5 Ubiquilin proteins (UBQLN1-4, UBQLN-L), which are evolutionarily conserved and structurally similar. UBQLN proteins have 3 functional domains: N-terminal ubiquitin-like domain (UBL), C-terminal ubiquitin-associated domain (UBA) and STI chaperone-like regions in the middle. Alterations in UBQLN1 gene have been detected in a variety of disorders ranging from Alzheimer’s disease to cancer. UBQLN1 has been largely studied in neurodegenerative disorders in the context of protein quality control. Several studies have hypothesized that the UBA domain of UBQLN1 binds to poly-ubiquitin chains of substrate and shuttles it to the proteasome via its UBL domain for degradation. UBQLN1 either facilitates degradation (Ataxin3, EPS15) or stabilizes (PSEN1/2, BCLb) substrates it binds to. The signal that determines this fate is unknown and there is conflicting data to support the existing working model of UBQLN1. Using BCLb as a model substrate, we characterized UBQLN1-substrate interaction. We identified the first two STI domains of UBQLN1 as critical for binding to BCLb. Interaction of UBQLN1 with BCLb is independent of ubiquitination of BCLb, but interaction with ubiquitin via UBA domain is required for its stabilization. Similarly, we showed that UBQLN1 interacts with IGF1R and ESYT2 through the STI domains and stabilizes these proteins through its UBA domain. Interactions that are not dependent on STI domains, for example UBL mediated interaction with PSMD4 and BAG6, do not appear to be stabilized by UBQLN1. We conclude that fate of substrates that UBQLN1 associates with, is interaction domain specific.