Hanna Kavaliova, Barbara Lecis, Demetra Ballardin, Laetitia Cobret, Thierry Bienvenu, Severine Morisset-Lopez, Heike Rebholz
{"title":"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。","authors":"Hanna Kavaliova, Barbara Lecis, Demetra Ballardin, Laetitia Cobret, Thierry Bienvenu, Severine Morisset-Lopez, Heike Rebholz","doi":"10.1515/hsz-2024-0162","DOIUrl":null,"url":null,"abstract":"<p><p>Poirier-Bienvenu neurodevelopmental syndrome is a neurodevelopmental disorder associated with <i>de novo</i> variants of the <i>CSNK2B</i> 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.</p>","PeriodicalId":8885,"journal":{"name":"Biological Chemistry","volume":" ","pages":""},"PeriodicalIF":2.9000,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Pathogenic missense variants of CSNK2B associated with Poirier-Bienvenu neurodevelopmental disorder impact differently on CK2 holoenzyme formation.\",\"authors\":\"Hanna Kavaliova, Barbara Lecis, Demetra Ballardin, Laetitia Cobret, Thierry Bienvenu, Severine Morisset-Lopez, Heike Rebholz\",\"doi\":\"10.1515/hsz-2024-0162\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Poirier-Bienvenu neurodevelopmental syndrome is a neurodevelopmental disorder associated with <i>de novo</i> variants of the <i>CSNK2B</i> 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.</p>\",\"PeriodicalId\":8885,\"journal\":{\"name\":\"Biological Chemistry\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":2.9000,\"publicationDate\":\"2025-05-05\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Biological Chemistry\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.1515/hsz-2024-0162\",\"RegionNum\":4,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Biological Chemistry","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1515/hsz-2024-0162","RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
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.
期刊介绍:
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