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蛋白的不稳定性是 ARID1B 致病变异的基础。

Protein destabilization underlies pathogenic missense mutations in ARID1B.

机构信息

Disease Area Oncology, Novartis Biomedical Research, Basel, Switzerland.

Disease Area Immunology, Novartis Biomedical Research, Basel, Switzerland.

出版信息

Nat Struct Mol Biol. 2024 Jul;31(7):1018-1022. doi: 10.1038/s41594-024-01229-2. Epub 2024 Feb 12.

DOI:10.1038/s41594-024-01229-2
PMID:38347147
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11257965/
Abstract

ARID1B is a SWI/SNF subunit frequently mutated in human Coffin-Siris syndrome (CSS) and it is necessary for proliferation of ARID1A mutant cancers. While most CSS ARID1B aberrations introduce frameshifts or stop codons, the functional consequence of missense mutations found in ARID1B is unclear. We here perform saturated mutagenesis screens on ARID1B and demonstrate that protein destabilization is the main mechanism associated with pathogenic missense mutations in patients with Coffin-Siris Syndrome.

摘要

ARID1B 是人类 Coffin-Siris 综合征（CSS）中频繁突变的 SWI/SNF 亚基，它是 ARID1A 突变型癌症增殖所必需的。虽然大多数 CSS ARID1B 异常都会引入移码或终止密码子，但在 ARID1B 中发现的错义突变的功能后果尚不清楚。我们在此对 ARID1B 进行饱和诱变筛选，证明蛋白不稳定是与 Coffin-Siris 综合征患者致病性错义突变相关的主要机制。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7920/11257965/d7f257b30868/41594_2024_1229_Fig12_ESM.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7920/11257965/d7f257b30868/41594_2024_1229_Fig12_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7920/11257965/b64942c65142/41594_2024_1229_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7920/11257965/715d79f51239/41594_2024_1229_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7920/11257965/bb90fc156d3e/41594_2024_1229_Fig3_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7920/11257965/9b78f85c6e49/41594_2024_1229_Fig4_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7920/11257965/d5408a8cfa5b/41594_2024_1229_Fig5_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7920/11257965/7b878602ec31/41594_2024_1229_Fig6_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7920/11257965/941fdd3c0815/41594_2024_1229_Fig7_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7920/11257965/c56b94ae5bce/41594_2024_1229_Fig8_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7920/11257965/f6193f81b344/41594_2024_1229_Fig9_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7920/11257965/18ab9972ecfc/41594_2024_1229_Fig10_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7920/11257965/5784a7033412/41594_2024_1229_Fig11_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7920/11257965/d7f257b30868/41594_2024_1229_Fig12_ESM.jpg

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