A novel mode of polymerization of α₁-proteinase inhibitor

TY - JOUR

T1 - A novel mode of polymerization of α1-proteinase inhibitor

AU - Marszal, Ewa

AU - Danino, Dganit

AU - Shrake, Andrew

PY - 2003/5/30

Y1 - 2003/5/30

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=0037490144&partnerID=8YFLogxK

U2 - 10.1074/jbc.M210720200

DO - 10.1074/jbc.M210720200

M3 - 文章

C2 - 12649292

AN - SCOPUS:0037490144

SN - 0021-9258

VL - 278

SP - 19611

EP - 19618

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

IS - 22

ER -