Nucleation of alpha 1-antichymotrypsin polymerization.
Alpha(1)-antichymotrypsin is an acute phase plasma protein and a member of the serpin superfamily. We show here that wildtype alpha(1)-antichymotrypsin forms polymers between the reactive center loop of one molecule and the beta-sheet A of a second at a rate that is dependent on protein concentration and the temperature of the reaction. The rate of polymerization was accelerated by seeding with polymers of alpha(1)-antichymotrypsin and a complex of alpha(1)-antichymotrypsin with an exogenous reactive loop peptide but not with reactive loop cleaved alpha(1)-antichymotrypsin or with polymers of other members of the serpin superfamily. Sonication of alpha(1)-antichymotrypsin polymers markedly increased the efficacy of seeding such that polymers were able to form under physiological conditions. Taken together, these data provide the first demonstration that serpin polymerization can result from seeding. This mechanism is analogous to the fibrillization of the Abeta(1-42) peptide and may be important in the deposition of alpha(1)-antichymotrypsin in the plaques of Alzheimer's disease.
Crowther
Damian C
DC
Neurology Unit, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Hills Road, Cambridge, CB2 2XY, United Kingdom. dcc26@cam.ac.uk
Serpell
Louise C
LC
Dafforn
Timothy R
TR
Gooptu
Bibek
B
Lomas
David A
DA
D000991:Antithrombins / Q000737:chemistry; D002942:Circular Dichroism; D006358:Hot Temperature; D006801:Humans; D008027:Light; D008970:Molecular Weight; D010446:Peptide Fragments / Q000737:chemistry / Q000648:ultrastructure; D011108:Polymers / Q000737:chemistry*; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D012542:Scattering, Radiation; D015842:Serine Proteinase Inhibitors / Q000737:chemistry; D013010:Sonication; D000514:alpha 1-Antichymotrypsin / Q000737:chemistry* / Q000648:ultrastructure
D000991:Antithrombins; D010446:Peptide Fragments; D011108:Polymers; D015842:Serine Proteinase Inhibitors; D000514:alpha 1-Antichymotrypsin