Processive extrusion of polypeptide loops by a Hsp100 disaggregase

doi:10.1038/s41586-020-1964-y

GSTDTAP > 地球科学

DOI	10.1038/s41586-020-1964-y
	Processive extrusion of polypeptide loops by a Hsp100 disaggregase
	Zhao, Peishen 1; Liang, Yi-Lynn 1; Belousoff, Matthew J.1; Deganutti, Giuseppe 2; Fletcher, Madeleine M.1; Willard, Francis S.3; Bell, Michael G.3; Christe, Michael E.3; Sloop, Kyle W.3; Inoue, Asuka 4; Truong, Tin T.1; Clydesdale, Lachlan 1; Furness, Sebastian G. B.1; Christopoulos, Arthur 1; Wang, Ming-Wei 5,6,7; Miller, Laurence J.8; Reynolds, Christopher A.2; Danev, Radostin 9; Sexton, Patrick M.1,7; Wootten, Denise 1,7
	2020-01-08
发表期刊	NATURE
ISSN	0028-0836
EISSN	1476-4687
出版年	2020
卷号	578 期号:7794 页码:317-+
文章类型	Article
语种	英语
国家	Netherlands; Germany
英文关键词	The ability to reverse protein aggregation is vital to cells(1,2). Hsp100 disaggregases such as ClpB and Hsp104 are proposed to catalyse this reaction by translocating polypeptide loops through their central pore(3,4). This model of disaggregation is appealing, as it could explain how polypeptides entangled within aggregates can be extracted and subsequently refolded with the assistance of Hsp70(4,5). However, the model is also controversial, as the necessary motor activity has not been identified(6-8) and recent findings indicate non-processive mechanisms such as entropic pulling or Brownian ratcheting(9,10). How loop formation would be accomplished is also obscure. Indeed, cryo-electron microscopy studies consistently show single polypeptide strands in the Hsp100 pore(11,12). Here, by following individual ClpB-substrate complexes in real time, we unambiguously demonstrate processive translocation of looped polypeptides. We integrate optical tweezers with fluorescent-particle tracking to show that ClpB translocates both arms of the loop simultaneously and switches to single-arm translocation when encountering obstacles. ClpB is notably powerful and rapid it exerts forces of more than 50 pN at speeds of more than 500 residues per second in bursts of up to 28 residues. Remarkably, substrates refold while exiting the pore, analogous to co-translational folding. Our findings have implications for protein-processing phenomena including ubiquitin-mediated remodelling by Cdc48 (or its mammalian orthologue p97)(13) and degradation by the 26S proteasome(14). A combination of optical tweezers and fluorescent-particle tracking is used to dissect the dynamics of the Hsp100 disaggregase ClpB, and show that the processive extrusion of polypeptide loops is the mechanistic basis of its activity.
领域	地球科学 ; 气候变化 ; 资源环境
收录类别	SCI-E
WOS记录号	WOS:000510138600005
WOS关键词	PROTEIN ; TRANSLOCATION ; MECHANISM ; CLPB
WOS类目	Multidisciplinary Sciences
WOS研究方向	Science & Technology - Other Topics
引用统计
文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/281257
专题	地球科学资源环境科学气候变化
作者单位	1.Monash Univ, Monash Inst Pharmaceut Sci, Drug Discovery Biol, Parkville, Vic, Australia; 2.Univ Essex, Sch Biol Sci, Colchester, Essex, England; 3.Eli Lilly & Co, Lilly Res Labs, Indianapolis, IN 46285 USA; 4.Tohoku Univ, Grad Sch Pharmaceut Sci, Sendai, Miyagi, Japan; 5.Chinese Acad Sci, Natl Ctr Drug Screening, Shanghai Inst Mat Med, Shanghai, Peoples R China; 6.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai, Peoples R China; 7.Fudan Univ, Sch Pharm, Shanghai, Peoples R China; 8.Mayo Clin, Scottsdale, AZ USA; 9.Univ Tokyo, Grad Sch Med, Bunkyo Ku, Tokyo, Japan
推荐引用方式 GB/T 7714	Zhao, Peishen,Liang, Yi-Lynn,Belousoff, Matthew J.,et al. Processive extrusion of polypeptide loops by a Hsp100 disaggregase[J]. NATURE,2020,578(7794):317-+.
APA	Zhao, Peishen.,Liang, Yi-Lynn.,Belousoff, Matthew J..,Deganutti, Giuseppe.,Fletcher, Madeleine M..,...&Wootten, Denise.(2020).Processive extrusion of polypeptide loops by a Hsp100 disaggregase.NATURE,578(7794),317-+.
MLA	Zhao, Peishen,et al."Processive extrusion of polypeptide loops by a Hsp100 disaggregase".NATURE 578.7794(2020):317-+.