Imbalances in p97 co-factor interactions in human proteinopathy
Imbalances in p97 co-factor interactions in human proteinopathy
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DOI：
10.1038/embor.2010.49
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发表时间：
2010-06-01
期刊：
影响因子：
7.7
通讯作者：
Buchberger, Alexander
中科院分区：
文献类型：
--
作者：
Fernandez-Saiz, Vanesa;Buchberger, Alexander
泛素选择性伴侣p97参与真核细胞的主要蛋白水解途径，并与几种人蛋白质病有关。此外，p97的突变导致疾病包容体肌病与骨骼和额颞痴呆症（IBMPFD）的肌病。 IBMPFD中泛素化蛋白的降解和病理聚集的分子基础降解和病理聚集尚不清楚。在这里，我们将扰动的co因子结合视为引起IBMPFD引起的突变体P97的常见缺陷。我们表明，IBMPFD突变诱导p97 N结构域的构象变化，P97 N结构域是调节副因素的主要结合位点。一致地，突变体p97蛋白表现出强烈改变的共同因素相互作用。具体而言，泛素连接酶E4b的结合减少，而双生素3的结合增强了，因此类似于3型脊椎队共济失调中突变蛋白3在p97上的积聚。 IBMPFD的特征以及其他涉及p97的蛋白质病的特征。
The ubiquitin-selective chaperone p97 is involved in major proteolytic pathways of eukaryotic cells and has been implicated in several human proteinopathies. Moreover, mutations in p97 cause the disorder inclusion body myopathy with Paget disease of bone and frontotemporal dementia (IBMPFD). The molecular basis underlying impaired degradation and pathological aggregation of ubiquitinated proteins in IBMPFD is unknown. Here, we identify perturbed co-factor binding as a common defect of IBMPFD-causing mutant p97. We show that IBMPFD mutations induce conformational changes in the p97 N domain, the main binding site for regulatory co-factors. Consistently, mutant p97 proteins exhibit strongly altered co-factor interactions. Specifically, binding of the ubiquitin ligase E4B is reduced, whereas binding of ataxin 3 is enhanced, thus resembling the accumulation of mutant ataxin 3 on p97 in spinocerebellar ataxia type 3. Our results suggest that imbalanced co-factor binding to p97 is a key pathological feature of IBMPFD and potentially of other proteinopathies involving p97.