Trans-Reduction of Cerebral Small Vessel Disease Proteins by Notch-Derived EGF-like Sequences.
Trans-Reduction of Cerebral Small Vessel Disease Proteins by Notch-Derived EGF-like Sequences.
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DOI：
10.3390/ijms23073671
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发表时间：
2022-03-27
影响因子：
5.6
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中科院分区：
文献类型：
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细胞外蛋白质的半胱氨酸氧化状态参与功能调节和疾病病理生理学。在最常见的遗传性痴呆、伴有皮质下梗死和白质脑病的常染色体显性遗传性脑动脉病（CADASIL）中，改变细胞外半胱氨酸数量的NOTCH 3突变已经暗示NOTCH 3半胱氨酸状态是脑血管平滑肌细胞病理学的潜在触发因素。在这份报告中，我们描述了NOTCH 3第二个EGF样结构域的一个新特性：它能够改变NOTCH 3胞外域的半胱氨酸氧化还原状态。对应于该序列的合成肽（N 0 TCH 3 N-末端片段2，NTF 2）容易以剂量和时间依赖性方式还原N 0 TCH 3 N-末端胞外域多肽。此外，NTF 2相对于EGF样结构域12-15以最高强度优先减少NOTCH 3的区域结构域。该过程需要NTF 2的半胱氨酸残基，并且还能够靶向选定的细胞外蛋白，包括TSP 2和CTSH。NOTCH 3中的CADASIL突变增加了对NTF 2促进的还原和细胞中产生的NOTCH 3的反式还原的易感性。此外，NTF 2与NOTCH 3胞外域形成复合物，并且切割的NOTCH 3与CADASIL患者的脑动脉中的NOTCH 3胞外域共定位。NTF 2减少血管蛋白的潜力和其对反式还原突变体NOTCH 3的增强偏好暗示了蛋白反式还原在脑血管病理状态如CADASIL中的作用。
Cysteine oxidation states of extracellular proteins participate in functional regulation and in disease pathophysiology. In the most common inherited dementia, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), mutations in NOTCH3 that alter extracellular cysteine number have implicated NOTCH3 cysteine states as potential triggers of cerebral vascular smooth muscle cytopathology. In this report, we describe a novel property of the second EGF-like domain of NOTCH3: its capacity to alter the cysteine redox state of the NOTCH3 ectodomain. Synthetic peptides corresponding to this sequence (NOTCH3 N-terminal fragment 2, NTF2) readily reduce NOTCH3 N-terminal ectodomain polypeptides in a dose- and time-dependent fashion. Furthermore, NTF2 preferentially reduces regional domains of NOTCH3 with the highest intensity against EGF-like domains 12–15. This process requires cysteine residues of NTF2 and is also capable of targeting selected extracellular proteins that include TSP2 and CTSH. CADASIL mutations in NOTCH3 increase susceptibility to NTF2-facilitated reduction and to trans-reduction by NOTCH3 produced in cells. Moreover, NTF2 forms complexes with the NOTCH3 ectodomain, and cleaved NOTCH3 co-localizes with the NOTCH3 ectodomain in cerebral arteries of CADASIL patients. The potential for NTF2 to reduce vascular proteins and the enhanced preference for it to trans-reduce mutant NOTCH3 implicate a role for protein trans-reduction in cerebrovascular pathological states such as CADASIL.
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影响因子：
2.9
作者：
Zhang, Xiaojie;Lee, Soo Jung;Young, Kelly Z.;Josephson, David A.;Geschwind, Michael D.;Wang, Michael M.
通讯作者：
Wang, Michael M.
影响因子：
6.6
作者：
Kim, Hee-Jung;Ha, Sura;Lee, Hee Yoon;Lee, Kong-Joo
通讯作者：
Lee, Kong-Joo
影响因子：
5.4
作者：
Okumura, Masaki;Saiki, Masatoshi;Hidaka, Yuji
通讯作者：
Hidaka, Yuji
影响因子：
3.7
作者：
Cartee NMP;Lee SJ;Keep SG;Wang MM
通讯作者：
Wang MM
在蛋白质组规模上绘制天然二硫键图谱。
影响因子：
48
作者：
Lu, Shan;Fan, Sheng-Bo;Dong, Meng-Qiu
通讯作者：
Dong, Meng-Qiu