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Identification of a HTT-specific binding motif in DNAJB1 essential for suppression and disaggregation of HTT
Nature Communications ( IF 16.6 ) Pub Date : 2022-08-10 , DOI: 10.1038/s41467-022-32370-5
S M Ayala Mariscal 1 , M L Pigazzini 1, 2 , Y Richter 3 , M Özel 3 , I L Grothaus 4, 5 , J Protze 1 , K Ziege 1 , M Kulke 6 , M ElBediwi 3 , J V Vermaas 6 , L Colombi Ciacchi 4, 5, 7 , S Köppen 4, 7 , F Liu 1 , J Kirstein 1, 3
Affiliation  

Huntington’s disease is a neurodegenerative disease caused by an expanded polyQ stretch within Huntingtin (HTT) that renders the protein aggregation-prone, ultimately resulting in the formation of amyloid fibrils. A trimeric chaperone complex composed of Hsc70, DNAJB1 and Apg2 can suppress and reverse the aggregation of HTTExon1Q48. DNAJB1 is the rate-limiting chaperone and we have here identified and characterized the binding interface between DNAJB1 and HTTExon1Q48. DNAJB1 exhibits a HTT binding motif (HBM) in the hinge region between C-terminal domains (CTD) I and II and binds to the polyQ-adjacent proline rich domain (PRD) of soluble as well as aggregated HTT. The PRD of HTT represents an additional binding site for chaperones. Mutation of the highly conserved H244 of the HBM of DNAJB1 completely abrogates the suppression and disaggregation of HTT fibrils by the trimeric chaperone complex. Notably, this mutation does not affect the binding and remodeling of any other protein substrate, suggesting that the HBM of DNAJB1 is a specific interaction site for HTT. Overexpression of wt DNAJB1, but not of DNAJB1H244A can prevent the accumulation of HTTExon1Q97 aggregates in HEK293 cells, thus validating the biological significance of the HBM within DNAJB1.



中文翻译:

DNAJB1中HTT特异性结合基序的鉴定对于抑制和分解HTT至关重要

亨廷顿氏病是一种神经退行性疾病,由亨廷顿蛋白 (HTT) 内扩大的 polyQ 拉伸引起,使蛋白质易于聚集,最终导致淀粉样蛋白原纤维的形成。由 Hsc70、DNAJB1 和 Apg2 组成的三聚体伴侣复合物可以抑制和逆转 HTTExon1Q 48的聚集。DNAJB1 是限速伴侣,我们在这里鉴定并表征了 DNAJB1 和 HTTExon1Q 48之间的结合界面. DNAJB1 在 C 末端结构域 (CTD) I 和 II 之间的铰链区显示 HTT 结合基序 (HBM),并与可溶性和聚集的 HTT 的 polyQ 相邻富含脯氨酸结构域 (PRD) 结合。HTT 的 PRD 代表了一个额外的伴侣结合位点。DNAJB1 的 HBM 的高度保守 H244 的突变完全消除了三聚体伴侣复合物对 HTT 原纤维的抑制和分解。值得注意的是,这种突变不影响任何其他蛋白质底物的结合和重塑,这表明 DNAJB1 的 HBM 是 HTT 的特定相互作用位点。wt DNAJB1 的过表达,而不是 DNAJB1 H244A的过表达可以阻止 HTTExon1Q 97的积累在 HEK293 细胞中聚集,从而验证了 HBM 在 DNAJB1 中的生物学意义。

更新日期:2022-08-10
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