与Poirier-Bienvenu神经发育障碍相关的CSNK2B致病性错义变异对CK2全酶形成的影响不同。

IF 2.9 4区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY
Hanna Kavaliova, Barbara Lecis, Demetra Ballardin, Laetitia Cobret, Thierry Bienvenu, Severine Morisset-Lopez, Heike Rebholz
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引用次数: 0

摘要

Poirier-Bienvenu神经发育综合征是一种与CSNK2B基因从头变异相关的神经发育障碍,其特征是智力残疾、发育迟缓、频繁癫痫发作等。虽然大多数变异是无义变异,导致蛋白质翻译流产,没有或截断CK2β,但也存在许多致病性错义变异。我们研究了四种变异对CK2全酶形成和活性的影响。我们发现锌指区变异导致蛋白质稳定性降低和亚细胞定位改变。不稳定性部分是由蛋白酶体和溶酶体降解介导的。我们进一步发现,这些位于锌指结构域的CK2β变体(p.a arg111pro, p.Cys137Phe)的同二聚化显著减少,而CK2α的结合似乎没有受到影响。其他变异,p.Asp32Asn和p.a arg86cys,不影响稳定性或CK2β/α结合。对于这些突变体,理解病理机制的关键可能取决于外部因素,如蛋白质-蛋白质相互作用的改变。我们得出结论,锌指结构域变异似乎破坏了蛋白质的稳定并影响了全酶的形成,有效地减少了称职的全息k2的池。在pobinding的背景下,我们的研究结果表明,锌指结构域变异可能影响细胞,类似于截断和剪接变异,减少全长CK2β的翻译。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Pathogenic missense variants of CSNK2B associated with Poirier-Bienvenu neurodevelopmental disorder impact differently on CK2 holoenzyme formation.

Poirier-Bienvenu neurodevelopmental syndrome is a neurodevelopmental disorder associated with de novo variants of the CSNK2B gene, characterized by intellectual disability, developmental delay, frequent seizures and more. While the majority of variants are nonsense variants leading to abortion of protein translation and no or truncated CK2β, many pathogenic missense variants also exist. We investigated the effect of four variants on CK2 holoenzyme formation and activity. We show that variants in the Zinc-finger region leads to reduced protein stability and altered subcellular localization. The instability is partly mediated by proteasomal and lysosomal degradation. We further show that homodimerization of these CK2β variants (p.Arg111Pro, p.Cys137Phe), localized within the Zinc-finger domain, is significantly reduced, while CK2α binding appears not affected. Other variants, p.Asp32Asn and p.Arg86Cys, did not affect stability or CK2β/α binding. For these mutants, the key to understanding the pathological mechanism may depend on external factors, such as altered protein-protein interaction. We conclude that Zinc-finger domain variants appear to destabilize the protein and affect holoenzyme formation, effectively reducing the pool of competent holoCK2. In the context of POBINDS, our findings suggest that Zinc-finger domain variants are likely to affect cells similarly to truncating and splicing variants with reduced translation of full-length CK2β.

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来源期刊
Biological Chemistry
Biological Chemistry 生物-生化与分子生物学
CiteScore
7.20
自引率
0.00%
发文量
63
审稿时长
4-8 weeks
期刊介绍: Biological Chemistry keeps you up-to-date with all new developments in the molecular life sciences. In addition to original research reports, authoritative reviews written by leading researchers in the field keep you informed about the latest advances in the molecular life sciences. Rapid, yet rigorous reviewing ensures fast access to recent research results of exceptional significance in the biological sciences. Papers are published in a "Just Accepted" format within approx.72 hours of acceptance.
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