A novel mode of polymerization of α1-proteinase inhibitor

Ewa Marszal, Dganit Danino, Andrew Shrake*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

14 Scopus citations


Patients homozygous for the Z mutant form of α1proteinase inhibitor (α1-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 α1-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 α1-PI monomer between the central strands of the A β-sheet of an adjacent monomer. This model derives primarily from two observations: peptides that are homologous with the RCL insert into the A β-sheet of α1-PI monomer and this insertion prevents α1-PI polymerization. Normal α1-PI monomer does not spontaneously polymerize; however, here we show that the disulfide-linked dimer of normal α1-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 α1-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 β-sheets may not occur during polymerization of this dimer.

Original languageEnglish
Pages (from-to)19611-19618
Number of pages8
JournalJournal of Biological Chemistry
Issue number22
StatePublished - 30 May 2003
Externally publishedYes


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