Neuronal low-density lipoprotein receptor-related protein 1 binds and endocytoses prion fibrils via receptor cluster 4

被引:48
|
作者
Jen, Angela [1 ]
Parkyn, Celia J. [1 ]
Mootoosamy, Roy C. [1 ]
Ford, Melanie J. [1 ]
Warley, Alice [2 ]
Liu, Qiang [3 ]
Bu, Guojun [3 ]
Baskakov, Ilia V. [4 ]
Moestrup, Soren [5 ]
McGuinness, Lindsay [6 ]
Emptage, Nigel [6 ]
Morris, Roger J. [1 ]
机构
[1] Kings Coll London, Wolfson Ctr Age Related Dis, London SE1 1UL, England
[2] Kings Coll London, Ctr Ultrastruct Imaging, London SE1 1UL, England
[3] Washington Univ, St Louis Childrens Hosp, Sch Med, Dept Pediat, St Louis, MO 63110 USA
[4] Univ Maryland, Ctr Med Biotechnol, Inst Biotechnol, Baltimore, MD 21201 USA
[5] Univ Aarhus, Dept Med Biochem, DK-8000 Aarhus C, Denmark
[6] Univ Oxford, Dept Pharmacol, Oxford OX1 3QT, England
基金
英国生物技术与生命科学研究理事会;
关键词
Endocytosis; LRP1; Lysosome; Neuron; Prion protein; HEPARAN-SULFATE PROTEOGLYCANS; CELL-SURFACE; INFECTIOUS PRIONS; APOLIPOPROTEIN-E; SCRAPIE ISOFORM; BETA-PEPTIDE; MICE; DISEASE; PRPSC; INTERNALIZATION;
D O I
10.1242/jcs.058099
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
For infectious prion protein (designated PrPSc) to act as a template to convert normal cellular protein (PrPC) to its distinctive pathogenic conformation, the two forms of prion protein (PrP) must interact closely. The neuronal receptor that rapidly endocytoses PrPC is the low-density lipoprotein receptor-related protein 1 (LRP1). We show here that on sensory neurons LRP1 is also the receptor that binds and rapidly endocytoses smaller oligomeric forms of infectious prion fibrils, and recombinant PrP fibrils. Although LRP1 binds two molecules of most ligands independently to its receptor clusters 2 and 4, PrPC and PrPSc fibrils bind only to receptor cluster 4. PrPSc fibrils out-compete PrPC for internalization. When endocytosed, PrPSc fibrils are routed to lysosomes, rather than recycled to the cell surface with PrPC. Thus, although LRP1 binds both forms of PrP, it traffics them to separate fates within sensory neurons. The binding of both to ligand cluster 4 should enable genetic modification of PrP binding without disrupting other roles of LRP1 essential to neuronal viability and function, thereby enabling in vivo analysis of the role of this interaction in controlling both prion and LRP1 biology.
引用
收藏
页码:246 / 255
页数:10
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