An ankyrin repeat chaperone targets toxic oligomers during amyloidogenesis

被引:1
|
作者
Gupta, Arpit [1 ]
Lu, Chuqi [1 ]
Wang, Feng [2 ]
Chou, Tsui-Fen [2 ]
Shan, Shu-ou [1 ]
机构
[1] CALTECH, Div Chem & Chem Engn, Pasadena, CA USA
[2] CALTECH, Div Biol & Biol Engn, Pasadena, CA USA
关键词
amyloid; amyloid beta peptide; ankyrin repeat proteins; chaperone; alpha-synuclein; AMYLOID-BETA OLIGOMERS; SIGNAL RECOGNITION PARTICLE; MEMBRANE-PROTEIN-AGGREGATE; MOLECULAR CHAPERONES; ACHIEVE NEUROPROTECTION; ALZHEIMERS-DISEASE; NUCLEATION; BINDING; MECHANISM; STRATEGY;
D O I
10.1002/pro.4728
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Numerous age-linked diseases are rooted in protein misfolding; this has motivated the development of small molecules and therapeutic antibodies that target the aggregation of disease-linked proteins. Here we explore another approach: molecular chaperones with engineerable protein scaffolds such as the ankyrin repeat domain (ARD). We tested the ability of cpSRP43, a small, robust, ATP- and cofactor-independent plant chaperone built from an ARD, to antagonize disease-linked protein aggregation. cpSRP43 delays the aggregation of multiple proteins including the amyloid beta peptide (A beta) associated with Alzheimer's disease and alpha-synuclein associated with Parkinson's disease. Kinetic modeling and biochemical analyses show that cpSRP43 targets early oligomers during A beta aggregation, preventing their transition to a selfpropagating nucleus on the fibril surface. Accordingly, cpSRP43 rescued neuronal cells from the toxicity of extracellular A beta 42 aggregates. The substratebinding domain of cpSRP43, composed primarily of the ARD, is necessary and sufficient to prevent A beta 42 aggregation and protect cells against A beta 42 toxicity. This work provides an example in which an ARD chaperone non-native to mammalian cells harbors anti-amyloidal activity, which may be exploited for bioengineering.
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页数:16
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