Arginine specific endopeptidases modify the aggregation properties of a synthetic peptide derived from Alzheimer beta/A4 amyloid.
A synthetic peptide corresponding to the first 28 amino acids of the Alzheimer disease amyloid beta/A4 peptide (3.2 kDa) aggregated to a high molecular weight (15 kDa) on SDS/urea polyacrylamide gels. Proteinase K, V8 protease, trypsin, and endopeptidase Lys-C readily degraded the aggregate. By contrast, when digested by endopeptidase Arg-C, a new polypeptide aggregate of higher molecular weight (16 kDa) was observed on denaturing gels without degraded smaller products. The new aggregate was comprised of three peptides: an intact beta/A4(1-28) and partially degraded peptides beta/A4(1-5) plus beta/A4(6-28). The results were confirmed by treatment of beta/A4 with other arginine-specific proteases: the gamma subunit of nerve growth factor and clostripain. The results indicate that arginine-specific proteases, including a growth factor processing enzyme, can nick aggregated beta/A4(1-28) amyloid and alter the configuration to produce a more complex aggregated form. If similar highly specific proteolytic mechanisms occur in the Alzheimer disease brain, the processing may promote the formation of high molecular weight aggregates that contribute to the development of relatively insoluble senile plaque core protein.
Honda
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Molecular Neurobiology Laboratory, McLean Hospital, Belmont, Massachusetts.
Marotta
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CA
D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D001120:Arginine / Q000378:metabolism*; D003546:Cysteine Endopeptidases; D004591:Electrophoresis, Polyacrylamide Gel; D019286:Endopeptidase K; D010450:Endopeptidases / Q000378:metabolism*; D015151:Immunoblotting; D008666:Metalloendopeptidases; D008970:Molecular Weight; D009414:Nerve Growth Factors / Q000737:chemistry; D009479:Neuropeptides / Q000737:chemistry*; D012697:Serine Endopeptidases; D013379:Substrate Specificity
D016229:Amyloid beta-Peptides; D009414:Nerve Growth Factors; D009479:Neuropeptides; D001120:Arginine; D010450:Endopeptidases; C044499:submandibular proteinase A; D012697:Serine Endopeptidases; C028344:glutamyl endopeptidase; D019286:Endopeptidase K; D003546:Cysteine Endopeptidases; C019913:clostripain; D008666:Metalloendopeptidases; C039830:peptidyl-Lys metalloendopeptidase