Amyloidogenesis: historical and modern observations point to heparan sulfate proteoglycans as a major culprit.
Amyloids are complex tissue deposits and each type is identified by one of 22 different proteins or peptides which become re-folded into non-native conformational intermediates and then assemble into fibrils of a highly regular structure. All amyloid deposits also contain apolipoprotein E (apoE) as well as the basement membrane (BM) components, serum amyloid P and heparan sulfate proteoglycans (HSPG), perlecan or agrin. These BM components likely contribute to the overall organization of amyloid fibrils and HSPG has been further implicated in the genesis of amyloid. A growing body of evidence, summarized in this review, suggests that heparan sulfate (HS) promotes fibrillogenesis by associating with the amyloid precursors and inducing the conformational change required for their assembly into fibrils. HS also remains associated with the nascent fibrils contributing to its stability. These activities of HS are likely mediated through specific binding sites on the precursor proteins which appear to have sequence characteristics that are unique to amyloid.
Ancsin
John B
JB
Department of Pathology, Queen's University, Syl and Molly Apps Research Center, Kingston General Hospital, Kingston, Ontario, Canada. 3jba1@post.queensu.ca
D000595:Amino Acid Sequence; D000682:Amyloid / Q000096:biosynthesis* / Q000737:chemistry; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis / Q000737:chemistry; D000686:Amyloidosis / Q000209:etiology* / Q000378:metabolism; D000818:Animals; D001485:Basement Membrane / Q000378:metabolism; D019812:Heparan Sulfate Proteoglycans / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D011485:Protein Binding
D000682:Amyloid; D016564:Amyloid beta-Protein Precursor; D019812:Heparan Sulfate Proteoglycans