IN-VITRO FIBRIL FORMATION FROM ALPHA(1)-ANTITRYPSIN-DERIVED C-TERMINAL PEPTIDES

Fragments from various proteolytically degraded precursor proteins can form beta-amyloid fibrils. We studied, by electron microscopy and qua ntitative Congo red binding, the ability of three synthetic peptides, corresponding to residues 359-374 (C-36), 370-374 (C-5) and 375-394 (C -20) from the C-terminal part of alpha(1)-antitrypsin (AAT) to form be ta-amyloid fibrils in vitro. The peptides C-36 and C-5 had a pronounce d tendency to form fibrils. C-20 lacked this property, suggesting that residues 359-375 and/or 370-374 are most critical for fibril formatio n. Native AAT added to peptide I-125-C-36 could bind and form complexe s with the peptide, resulting in inhibition of amyloid fibril formatio n. Moreover, native AAT added to preformed fibrils induced disaggregat ion of fibrillar structures. The structural rearrangements of AAT that occurred during this 'autointeraction' included polymerization of the serpin, and an increase of its thermal stability. Also, following int eraction, an increase (20-40%) of AAT's antielastase activity was note d. The demonstration of an in vitro P-amyloid fibril formation from th e AAT derived C-terminal peptides C-36 and C-5 and its regulation by t he intact AAT molecule may have important in vivo implications.