The spontaneous polymerization of plasminogen activator inhibitor type-2 and Z-antitrypsin are due to different molecular aberrations.
The wild-type form of plasminogen activator inhibitor type-2 (PAI-2) and the pathogenic Z-mutant of alpha(1)-antitrypsin (alpha(1)AT) are serpins that spontaneously polymerize by the loop-sheet mechanism. Compared to the consensus serpin sequence, both PAI-2 and Z-alpha(1)AT have deviations in the so-called breach region located at the top of the A beta-sheet. In the case of Z-alpha(1)AT, conformational perturbations caused by a single amino acid substitution result in polymerization in vivo and predisposes to disease. To test whether the polymerization of PAI-2 is due to aberrations in the breach region, we constructed substitution mutants of PAI-2 with conserved residues in this region. Analysis of the mutants revealed that deviations in the breach region modulate but are not the major cause of PAI-2 polymerization. Rather, PAI-2 exists in a highly polymerogenic conformation and does not require conformational rearrangements before polymerization can take place.
Wilczynska
Malgorzata
M
Department of Medical Biochemistry and Biophysics, Umeå University, Sweden.
Lobov
Sergei
S
Ny
Tor
T
D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D017396:Plasminogen Activator Inhibitor 2 / Q000737:chemistry*; D017433:Protein Structure, Secondary; D015843:Serpins / Q000737:chemistry; D014568:Urokinase-Type Plasminogen Activator / Q000737:chemistry / Q000378:metabolism; D000515:alpha 1-Antitrypsin / Q000737:chemistry*
D017396:Plasminogen Activator Inhibitor 2; D015843:Serpins; D000515:alpha 1-Antitrypsin; D014568:Urokinase-Type Plasminogen Activator