Mice expressing ApoA-IIF rather than ApoA-IIC are resistant to AApoAII amyloidosis.
•Cryo-EM structures of ApoA-IIC-derived fibrils reveal the pathogenic fibril fold.
•The mutations in ApoA-IIF destabilise the fold of the fibril proteins.
•Our data explain previous observation of the importance of the Asn62Lys mutation.
•Our study supports the idea that disease arises from specific fibril morphologies.
AbstractAmyloid resistance is the inability or the reduced susceptibility of an organism to develop amyloidosis. In this study we have analysed the molecular basis of the resistance to systemic AApoAII amyloidosis, which arises from the formation of amyloid fibrils from apolipoprotein A-II (ApoA-II). The disease affects humans and animals, including SAMR1C mice that express the C allele of ApoA-II protein, whereas other mouse strains are resistant to development of amyloidosis due to the expression of other ApoA-II alleles, such as ApoA-IIF. Using cryo-electron microscopy, molecular dynamics simulations and other methods, we have determined the structures of pathogenic AApoAII amyloid fibrils from SAMR1C mice and analysed the structural effects of ApoA-IIF-specific mutational changes. Our data show that these changes render ApoA-IIF incompatible with the specific fibril morphologies, with which ApoA-II protein can become pathogenic in vivo.
Keywordsaggregation
protein misfolding
amyloidosis
apolipoprotein
amyloid resistance
AbbreviationsApoA-IIapolipoprotein A-II
HDLhigh density lipoprotein
cryo-EMcryo-electron microscopy
PTMpost translational modification
TEMtransmission electron microscopy
FSCFourier shell correlation
RMSDroot mean square deviation
© 2024 The Author(s). Published by Elsevier Ltd.
留言 (0)