Low density lipoprotein misfolding and amyloidogenesis.
In early atherogenesis, subendothelial retention of lipidic droplets is associated with an inflammatory response-to-injury, culminating in the formation of foam cells and plaque. Low density lipoprotein (LDL) is the main constituent of subendothelial lipidic droplets. The process is believed to occur following LDL modification. Searching for a modified LDL in plasma, electronegative LDL [LDL(-)] was identified and found to be associated with major risk biomarkers. The apoprotein in LDL(-) is misfolded, and we show here that this modification primes the aggregation of native LDL, conforming to the typical pattern of protein amyloidogenesis. After a lag phase, whose length depends on LDL(-) concentration, light scattering and atomic force microscopy reveal early exponential growth of intermediate globules, which evolve into fibrils. These globules are remarkably similar to subendothelial droplets in atheromatous lesions and different from those produced by oxidation or biochemical manipulation. During aggregation, ellipticity and tryptophan fluorescence measurements reveal a domino-style spread of apoprotein misfolding from LDL(-) to all of the LDL. Computational analysis of the apoprotein primary sequence predicts an unstable, aggregation-prone domain in the regulatory alpha2 region. Apoprotein misfolding well represents an LDL modification able to transform this cholesterol carrier into a trigger for a response-to-injury in the artery wall.
Parasassi
Tiziana
T
Istituto di Neurobiologia e Medicina Molecolare, CNR, Via del Fosso del Cavaliere 100, 00133 Rome, Italy. t.parasassi@inmm.cnr.it
De Spirito
Marco
M
Mei
Giampiero
G
Brunelli
Roberto
R
Greco
Giulia
G
Lenzi
Laura
L
Maulucci
Giuseppe
G
Nicolai
Eleonora
E
Papi
Massimiliano
M
Arcovito
Giuseppe
G
Tosatto
Silvio C E
SC
Ursini
Fulvio
F
D000328:Adult; D000686:Amyloidosis / Q000235:genetics*; D050197:Atherosclerosis / Q000235:genetics; D008078:Cholesterol, LDL / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008077:Lipoproteins, LDL / Q000097:blood / Q000235:genetics*; D020894:Microfibrils / Q000648:ultrastructure; D008875:Middle Aged; D017510:Protein Folding; D012016:Reference Values
D008078:Cholesterol, LDL; D008077:Lipoproteins, LDL