A new Karyopherin-β2 binding PY-NLS epitope of HNRNPH2 is linked to neurodevelopmental disorders.
A new Karyopherin-β2 binding PY-NLS epitope of HNRNPH2 is linked to neurodevelopmental disorders.
复制标题
HNRNPH2 的新核传递蛋白-β2 结合 PY-NLS 表位与神经发育障碍有关。
DOI：
10.1101/2023.01.20.524964
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Chook,YuhMin
中科院分区：
文献类型：
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作者：
Gonzalez,Abner;Kim,HongJoo;Freibaum,BrianD;JoyceFung,HoYee;Brautigam,ChadA;Taylor,JPaul;Chook,YuhMin
HNRNPH 2脯氨酸-酪氨酸核定位信号（PY-NLS）在HNRNPH 2相关的X连锁神经发育障碍中发生突变，导致正常的核HNRNPH 2在细胞质中积累。我们解析了与HNRNPH 2 PY-NLS结合的Karyopherin-β2/Transportin-1的冷冻电镜（cryo-EM）结构，以了解疾病中的重要蛋白-NLS识别和破坏。HNRNPH 2206 RPGPY 210是典型的R-X2-4-P-Y基序，其包含PY-NLS表位2和3，随后是在残基211 DRP 213处的另外的Karyopherin-β2结合表位，我们称为表位4;对于PY-NLS表位1不存在密度。表位2-4处的疾病变体突变损害了Karyopherin-β2结合并导致细胞中异常的细胞质积累，强调了核输入缺陷在疾病中的作用。序列/结构分析表明，强PY-NLS表位4是罕见的，因此仅限于HNRNPH 2、HNRNPH 1和HNRNPF的近亲。表位4结合热点Karyopherin-β2 W373对应于神经发育异常中的病理变异位点Karyopherin-β2b/Transportin-2 W370，提示Karyopherin-β2b/Transportin-2-HNRNPH 2/H1/F相互作用可能在异常中受损。
The HNRNPH2 proline-tyrosine nuclear localization signal (PY-NLS) is mutated inHNRNPH2-related X-linked neurodevelopmental disorder, causing the normally nuclear HNRNPH2 to accumulate in the cytoplasm. We solved the cryoelectron microscopy (cryo-EM) structure of Karyopherin-β2/Transportin-1 bound to the HNRNPH2 PY-NLS to understand importin-NLS recognition and disruption in disease. HNRNPH2206RPGPY210is a typical R-X2-4-P-Y motif comprising PY-NLS epitopes 2 and 3, followed by an additional Karyopherin-β2-binding epitope, we term epitope 4, at residues211DRP213; no density is present for PY-NLS epitope 1. Disease variant mutations at epitopes 2-4 impair Karyopherin-β2 binding and cause aberrant cytoplasmic accumulation in cells, emphasizing the role of nuclear import defect in disease. Sequence/structure analysis suggests that strong PY-NLS epitopes 4 are rare and thus far limited to close paralogs of HNRNPH2, HNRNPH1, and HNRNPF. Epitope 4-binidng hotspot Karyopherin-β2 W373 corresponds to close paralog Karyopherin-β2b/Transportin-2 W370, a pathological variant site in neurodevelopmental abnormalities, suggesting that Karyopherin-β2b/Transportin-2-HNRNPH2/H1/F interactions may be compromised in the abnormalities.