title: A novel mode of polymerization of alpha1-proteinase inhibitor.
abstract: Patients homozygous for the Z mutant form of alpha1-proteinase inhibitor (alpha1-PI) have an increased risk for the development of liver disease because of the accumulation in hepatocytes of inclusion bodies containing linear polymers of mutant alpha1-PI. The most widely accepted model of polymerization proposes that a linear, head-to-tail polymer forms by sequential insertion of the reactive center loop (RCL) of one alpha1-PI monomer between the central strands of the A beta-sheet of an adjacent monomer. This model derives primarily from two observations: peptides that are homologous with the RCL insert into the A beta-sheet of alpha1-PI monomer and this insertion prevents alpha1-PI polymerization. Normal alpha1-PI monomer does not spontaneously polymerize; however, here we show that the disulfide-linked dimer of normal alpha1-PI spontaneously forms linear polymers in buffer. The monomers within this dimer are joined head-to-head. Thus, the arrangement of monomers in these polymers must be different from that predicted by the loop-A sheet model. Therefore, we propose a new model for alpha1-PI polymer. In addition, polymerization of disulfide-linked dimer is not inhibited by the presence of the peptide even though dimer appears to interact with the peptide. Thus, RCL insertion into A beta-sheets may not occur during polymerization of this dimer.
authors.affiliation: Division of Hematology, Office of Blood Research and Review, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892, USA.
authors.forename: Ewa
authors.initials: E
authors.lastname: Marszal
authors.forename: Dganit
authors.initials: D
authors.lastname: Danino
authors.forename: Andrew
authors.initials: A
authors.lastname: Shrake
mesh_terms: D000595:Amino Acid Sequence; D001704:Biopolymers / Q000378:metabolism*; D002850:Chromatography, Gel; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D008854:Microscopy, Electron; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017510:Protein Folding; D000515:alpha 1-Antitrypsin / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure
chemical_list: D001704:Biopolymers; D000515:alpha 1-Antitrypsin