Structural prerequisites for serum amyloid A fibril formation.
Most studies of experimental amyloid A protein (AA) amyloidosis in mice have been performed in type A mice with BALB/c as the prototype. In these mice the products of two genes, SAA1 and SAA2, are the major apo-SAA isoforms on high density lipoprotein (HDL). Of these two isoforms, that differ at nine amino acids, only apo-SAA2 is rapidly cleared and deposited as amyloid fibrils. No mouse strain has ever been shown to be completely resistant to amyloid induction. We have found the CE/J mouse strain to be exceedingly resistant to amyloidogenesis. Data indicate that this resistance is not due to a lack of apo-SAA synthesis but rather resides in the unique apo-SAA isoform in this strain. CE/J mice have a single major apo-SAA isoform (pI 6.15) the product of a single gene. This is a hybrid molecule with features of both apo-SAA1 and apo-SAA2, differing from the latter at only six amino acids. When CD studies were performed to explore the structural relationship of this isoform to apo-SAA1 and apo-SAA2, we found that when bound to heparan sulfate proteoglycan the CE/J pI 6.15 isoform fails to undergo the beta-sheet folding typical for apo-SAA2. This evidence suggests that the folding effect of heparan sulfate proteoglycan on apo-SAA2 is important in amyloid formation.
Department of Medicine, University of Kentucky Medical Center, Lexington 40536.
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de Beer
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de Beer
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McCubbin
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Kay
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Kindy
D000595:Amino Acid Sequence; D000818:Animals; D001059:Apoproteins / Q000096:biosynthesis / Q000235:genetics; D015139:Blotting, Southern; D003001:Cloning, Molecular; D004247:DNA / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism; D005260:Female; D015723:Gene Library; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D005810:Multigene Family; D015183:Restriction Mapping; D017386:Sequence Homology, Amino Acid; D012689:Sequence Homology, Nucleic Acid; D000685:Serum Amyloid A Protein / Q000096:biosynthesis* / Q000235:genetics
D001059:Apoproteins; D000685:Serum Amyloid A Protein; D004247:DNA