Nucleation of α1-antichymotrypsin polymerization

D.C. Crowther; L.C. Serpell; T.R. Dafforn; B. Gooptu; D.A. Lomas

doi:10.1021/bi0259305

Nucleation of α₁-antichymotrypsin polymerization

D.C. Crowther, L.C. Serpell, T.R. Dafforn, B. Gooptu, D.A. Lomas

Cambridge Institute for Medical Research

Research output: Contribution to journal › Article › peer-review

32 Citations (Scopus)

Abstract

Alpha-antichymotrypsin is an acute phase plasma protein and a member of the serpin superfamily. We show here that wildtype α-antichymotrypsin forms polymers between the reactive center loop of one molecule and the β-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 α-antichymotrypsin and a complex of α-antichymotrypsin with an exogenous reactive loop peptide but not with reactive loop cleaved α-antichymotrypsin or with polymers of other members of the serpin superfamily. Sonication of α-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 Aβ peptide and may be important in the deposition of α-antichymotrypsin in the plaques of Alzheimer's disease.

Original language	English
Pages (from-to)	2355-2363
Number of pages	9
Journal	Biochemistry
Volume	42
Issue number	8
DOIs	https://doi.org/10.1021/bi0259305
Publication status	Published - 4 Feb 2003

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abstract = "Alpha-antichymotrypsin is an acute phase plasma protein and a member of the serpin superfamily. We show here that wildtype α-antichymotrypsin forms polymers between the reactive center loop of one molecule and the β-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 α-antichymotrypsin and a complex of α-antichymotrypsin with an exogenous reactive loop peptide but not with reactive loop cleaved α-antichymotrypsin or with polymers of other members of the serpin superfamily. Sonication of α-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 Aβ peptide and may be important in the deposition of α-antichymotrypsin in the plaques of Alzheimer's disease.",

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AU - Crowther, D.C.

AU - Serpell, L.C.

AU - Dafforn, T.R.

AU - Gooptu, B.

AU - Lomas, D.A.

PY - 2003/2/4

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N2 - Alpha-antichymotrypsin is an acute phase plasma protein and a member of the serpin superfamily. We show here that wildtype α-antichymotrypsin forms polymers between the reactive center loop of one molecule and the β-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 α-antichymotrypsin and a complex of α-antichymotrypsin with an exogenous reactive loop peptide but not with reactive loop cleaved α-antichymotrypsin or with polymers of other members of the serpin superfamily. Sonication of α-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 Aβ peptide and may be important in the deposition of α-antichymotrypsin in the plaques of Alzheimer's disease.

AB - Alpha-antichymotrypsin is an acute phase plasma protein and a member of the serpin superfamily. We show here that wildtype α-antichymotrypsin forms polymers between the reactive center loop of one molecule and the β-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 α-antichymotrypsin and a complex of α-antichymotrypsin with an exogenous reactive loop peptide but not with reactive loop cleaved α-antichymotrypsin or with polymers of other members of the serpin superfamily. Sonication of α-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 Aβ peptide and may be important in the deposition of α-antichymotrypsin in the plaques of Alzheimer's disease.

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Nucleation of α₁-antichymotrypsin polymerization

Abstract

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