Multivalent DNA and nucleosome acidic patch interactions specify VRK1 mitotic localization and activity.
Multivalent DNA and nucleosome acidic patch interactions specify VRK1 mitotic localization and activity.
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DOI：
10.1093/nar/gkac198
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发表时间：
2022-05-06
影响因子：
14.9
通讯作者：
McGinty, Robert K.
中科院分区：
文献类型：
--
作者：
Budziszewski, Gabrielle R.;Zhao, Yani;Spangler, Cathy J.;Kedziora, Katarzyna M.;Williams, Michael R.;Azzam, Dalal N.;Skrajna, Aleksandra;Koyama, Yuka;Cesmat, Andrew P.;Simmons, Holly C.;Arteaga, Eyla C.;Strauss, Joshua D.;Kireev, Dmitri;McGinty, Robert K.
染色质激酶的一个关键作用是在有丝分裂期间磷酸化组蛋白尾部以时空调节细胞分裂。牛痘相关激酶1（VRK 1）是一种丝氨酸-苏氨酸激酶，其磷酸化组蛋白H3苏氨酸3（H3 T3）沿着其它基于染色质的靶标。虽然结构研究已经确定了几类组蛋白修饰酶如何与核小体结合并发挥作用，但激酶参与染色质的机制在很大程度上尚不清楚。在这里，我们配对冷冻电子显微镜与生物化学和细胞分析，以证明VRK 1与连接DNA和核小体酸性补丁相互作用，磷酸化H3 T3。VRK 1的酸性斑块结合是由富含精氨酸的柔性C-末端尾介导的。VRK 1中酸性斑块识别基序的纯合错义和无义突变是罕见的成人型远端脊髓性肌萎缩症的病因。我们发现，这些VRK 1突变干扰核小体酸性补丁结合，导致VRK 1在有丝分裂过程中的错误定位，从而提供了一个潜在的新的发病机制的分子机制。
A key role of chromatin kinases is to phosphorylate histone tails during mitosis to spatiotemporally regulate cell division. Vaccinia-related kinase 1 (VRK1) is a serine–threonine kinase that phosphorylates histone H3 threonine 3 (H3T3) along with other chromatin-based targets. While structural studies have defined how several classes of histone-modifying enzymes bind to and function on nucleosomes, the mechanism of chromatin engagement by kinases is largely unclear. Here, we paired cryo-electron microscopy with biochemical and cellular assays to demonstrate that VRK1 interacts with both linker DNA and the nucleosome acidic patch to phosphorylate H3T3. Acidic patch binding by VRK1 is mediated by an arginine-rich flexible C-terminal tail. Homozygous missense and nonsense mutations of this acidic patch recognition motif in VRK1 are causative in rare adult-onset distal spinal muscular atrophy. We show that these VRK1 mutations interfere with nucleosome acidic patch binding, leading to mislocalization of VRK1 during mitosis, thus providing a potential new molecular mechanism for pathogenesis.
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影响因子：
4.6
作者：
Couñago RM;Allerston CK;Savitsky P;Azevedo H;Godoi PH;Wells CI;Mascarello A;de Souza Gama FH;Massirer KB;Zuercher WJ;Guimarães CRW;Gileadi O
通讯作者：
Gileadi O
影响因子：
0.8
作者：
Herrmann, Christin;Avgousti, Daphne C.;Weitzman, Matthew D.
通讯作者：
Weitzman, Matthew D.
影响因子：
4.4
作者：
JORGENSEN, WL;CHANDRASEKHAR, J;KLEIN, ML
通讯作者：
KLEIN, ML
DOI：
10.1107/s2059798318006551
发表时间：
2018-06-01
期刊：
Acta crystallographica. Section D, Structural biology
影响因子：
--
作者：
Afonine PV;Poon BK;Read RJ;Sobolev OV;Terwilliger TC;Urzhumtsev A;Adams PD
通讯作者：
Adams PD
影响因子：
4.4
作者：
ESSMANN, U;PERERA, L;PEDERSEN, LG
通讯作者：
PEDERSEN, LG