The strand exchange domain of tumor suppressor PALB2 is intrinsically disordered and promotes oligomerization-dependent DNA compaction

IF 4.6 2区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

iScience Pub Date : 2024-10-28 DOI:10.1016/j.isci.2024.111259

Yevhenii Kyriukha , Maxwell B. Watkins , Jennifer M. Redington , Nithya Chintalapati , Abhishek Ganti , Reza Dastvan , Vladimir N. Uversky , Jesse B. Hopkins , Nicola Pozzi , Sergey Korolev

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引用次数: 0

Abstract

The partner and localizer of BRCA2 (PALB2) is a scaffold protein linking BRCA1 with BRCA2 and RAD51 during homologous recombination (HR). PALB2 interaction with DNA strongly enhances HR in cells, while the PALB2 DNA-binding domain (PALB2-DBD) supports DNA strand exchange in vitro. We determined that PALB2-DBD is intrinsically disordered beyond a single N-terminal α-helix. Coiled-coil mediated dimerization is stabilized by interaction between intrinsically disordered regions (IDRs) leading to a 2-fold structural compaction. Single-stranded (ss)DNA binding promotes additional structural compaction and protein tetramerization. Using confocal single-molecule FRET, we observed bimodal and oligomerization-dependent compaction of ssDNA bound to PALB2-DBD, suggesting a novel strand exchange mechanism. Bioinformatics analysis and preliminary observations indicate that PALB2 forms protein-nucleic acids condensates. Intrinsically disordered DBDs are prevalent in the human proteome. PALB2-DBD and similar IDRs may use a chaperone-like mechanism to aid formation and resolution of DNA and RNA multichain intermediates during DNA replication, repair and recombination.

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肿瘤抑制因子 PALB2 的链交换结构域具有内在无序性，可促进寡聚化依赖性 DNA 压实

BRCA2 的伙伴和定位器（PALB2）是同源重组（HR）过程中连接 BRCA1 与 BRCA2 和 RAD51 的支架蛋白。PALB2 与 DNA 的相互作用可强烈增强细胞中的 HR，而 PALB2 DNA 结合域（PALB2-DBD）则支持体外 DNA 链交换。我们确定，PALB2-DBD 除了单个 N 端 α 螺旋外，在本质上是无序的。盘绕线圈介导的二聚化通过内在无序区（IDRs）之间的相互作用而稳定，从而导致结构压缩 2 倍。单链（ss）DNA 的结合促进了额外的结构压实和蛋白质四聚化。利用共聚焦单分子 FRET，我们观察到了与 PALB2-DBD 结合的 ssDNA 的双峰和寡聚依赖性压实，这表明了一种新的链交换机制。生物信息学分析和初步观察表明，PALB2 形成了蛋白质-核酸凝聚体。本质上无序的 DBD 在人类蛋白质组中非常普遍。PALB2-DBD和类似的IDRs可能利用类似于伴侣的机制，在DNA复制、修复和重组过程中帮助DNA和RNA多链中间体的形成和解析。

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来源期刊

iScience Multidisciplinary-Multidisciplinary

CiteScore

7.20

自引率

1.70%

发文量

1972

审稿时长

6 weeks

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