A novel mode of polymerization of alpha(1)-proteinase inhibitor

作者：Marszal E; Danino D; Shrake A^*

来源：Journal of Biological Chemistry, 2003, 278(22): 19611-19618.

DOI：10.1074/jbc.M210720200

Patients homozygous for the Z mutant form of alpha(1)-proteinase inhibitor (alpha(1)-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 alpha(1)-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 alpha(1)-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 alpha(1)-PI monomer and this insertion prevents alpha(1)-PI polymerization. Normal alpha(1)-PI monomer does not spontaneously polymerize; however, here we show that the disulfide-linked dimer of normal alpha(1)-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 alpha(1)-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.

• 出版日期2003-5-30