Perrault syndrome type 3 caused by diverse molecular defects in CLPP.
Perrault syndrome type 3 caused by diverse molecular defects in CLPP.
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DOI：
10.1038/s41598-018-30311-1
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发表时间：
2018-08-27
影响因子：
4.6
通讯作者：
Dougan DA
中科院分区：
文献类型：
--
作者：
Brodie EJ;Zhan H;Saiyed T;Truscott KN;Dougan DA
线粒体蛋白质稳态（proteostasis）的维持对于正确的细胞功能至关重要。最近，在Perrault综合征3（PRLTS 3）患者中发现了线粒体蛋白酶CLPP的几个突变。这些突变可以被排列成两组，聚集在同源解折叠酶CLPX的对接位点（疏水口袋，Hp）附近的那些（即T145 P和C147 S）和邻近肽酶活性位点的那些（即Y229 D）。在这里，我们报告的生化后果的突变在这两个地区。Y229 D突变体不仅抑制CLPP-肽酶活性，而且意外地还阻止CLPX-对接，从而阻断肽和蛋白质底物的周转。相比之下，Hp突变导致CLPP的一系列生化缺陷，从C147 S突变体的CLPP活性没有可观察到的变化，到“功能获得性”突变体T145 P的大多数活性的急剧破坏-包括寡聚体组装的丧失和肽酶活性的增强。
The maintenance of mitochondrial protein homeostasis (proteostasis) is crucial for correct cellular function. Recently, several mutations in the mitochondrial protease CLPP have been identified in patients with Perrault syndrome 3 (PRLTS3). These mutations can be arranged into two groups, those that cluster near the docking site (hydrophobic pocket, Hp) for the cognate unfoldase CLPX (i.e. T145P and C147S) and those that are adjacent to the active site of the peptidase (i.e. Y229D). Here we report the biochemical consequence of mutations in both regions. The Y229D mutant not only inhibited CLPP-peptidase activity, but unexpectedly also prevented CLPX-docking, thereby blocking the turnover of both peptide and protein substrates. In contrast, Hp mutations cause a range of biochemical defects in CLPP, from no observable change to CLPP activity for the C147S mutant, to dramatic disruption of most activities for the “gain-of-function” mutant T145P - including loss of oligomeric assembly and enhanced peptidase activity.
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影响因子：
3.5
作者：
Chatzispyrou IA;Alders M;Guerrero-Castillo S;Zapata Perez R;Haagmans MA;Mouchiroud L;Koster J;Ofman R;Baas F;Waterham HR;Spelbrink JN;Auwerx J;Mannens MM;Houtkooper RH;Plomp AS
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Plomp AS
影响因子：
4.4
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通讯作者：
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影响因子：
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作者：
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通讯作者：
Ortiz-Lombardia, Miguel
影响因子：
9.8
作者：
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通讯作者：
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影响因子：
3.5
作者：
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通讯作者：
Gregersen, N