Highly Selective Activation of Heat Shock Protein 70 by Allosteric Regulation Provides an Insight into Efficient Neuroinflammation Inhibition

Autor: Li-Chao Wang, Li-Xi Liao, Hai-Ning Lv, Dan Liu, Wei Dong, Jian Zhu, Jin-Feng Chen, Meng-Ling Shi, Ge Fu, Xiao-Min Song, Yong Jiang, Ke-Wu Zeng, Peng-Fei Tu
Jazyk: angličtina
Rok vydání: 2017
Předmět:
Zdroj: EBioMedicine, Vol 23, Iss C, Pp 160-172 (2017)
Druh dokumentu: article
ISSN: 2352-3964
DOI: 10.1016/j.ebiom.2017.08.011
Popis: Heat shock protein 70 (Hsp70) is widely involved in immune disorders, making it as an attractive drug target for inflammation diseases. Nonselective induction of Hsp70 upregulation for inflammation therapy could cause extensive interference in inflammation-unrelated protein functions, potentially resulting in side effects. Nevertheless, direct pharmacological activation of Hsp70 via targeting specific functional amino acid residue may provide an insight into precise Hsp70 function regulation and a more satisfactory treatment effect for inflammation, which has not been extensively focused. Here we show a cysteine residue (Cys306) for selective Hsp70 activation using natural small-molecule handelin. Covalent modification of Cys306 significantly elevates Hsp70 activity and shows more satisfactory anti-neuroinflammation effects. Mechanism study reveals Cys306 modification by handelin induces an allosteric regulation to facilitate adenosine triphosphate hydrolysis capacity of Hsp70, which leads to the effective blockage of subsequent inflammation signaling pathway. Collectively, our study offers some insights into direct pharmacological activation of Hsp70 by specially targeting functional cysteine residue, thus providing a powerful tool for accurately modulating neuroinflammation pathogenesis in human with fewer undesirable adverse effects.
Databáze: Directory of Open Access Journals