The Structure of á1-Proteinase Inhibitor Polymer: Facts and Hypothesis pp.199-210
Authors: (Ewa Marszal—Division of Hematology, Office of Blood Research and Review, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland)
Abstract: The metastable structure of a serpin 1-proteinase inhibitor (1-PI) makes it prone to conformational changes as a result of certain mutations and under mild denaturing conditions. Polymers of several variants of 1-PI, e.g., the most clinically relevant Z variant, accumulate in the liver and are believed to be the underlying cause of the liver disease associated with 1-PI deficiency. Such polymers have also been found in the circulation and in the lung. The structure of these polymers, which is important for structure-based drug design, remains unknown. The historically first and generally accepted model of the 1-PI polymers, the loop-A sheet model, which assumes insertion of the reactive center loop (RCL) of one 1-PI molecule between the central strands of the A -sheet of another molecule, has never been proven. In addition, this model is inconsistent with resonance energy transfer data obtained for heteropolymers formed from the Z and S variants. It is also difficult to envision how this model or even the more compact loop-A sheet model, deduced from fluorescence data obtained for the Z and S variant heteropolymers, can be compatible with electron microscopy (EM) images, which show apparently flexible polymer chains. Two other polymer models were deduced from the interactions seen between molecules in the crystals of two other serpins, antithrombin (AT) and plasminogen activator inhibitor-1 (PAI-1), which demonstrated the ability of the reactive center loop (RCL) to assume the -strand conformation and to extend the C or A -sheet in a neighboring molecule by formation of an additional edge strand. This became the ground for the loop-C sheet and strand s7A models of the polymer, although the interactions seen in crystals appear not to be stable in solution and, thus, appear not to reflect interactions existing in 1-PI polymers, which actually are stable. The focus of this paper is to review the observations used to support the proposed models and to revisit the wealth of literature data in search for unexplained observations and possible new interpretations. I also put forward the hypothesis that a fusion of -sheets, rather than insertion of the reactive center loop into a -sheet, may underlie the polymerization process of 1-PI. This hypothesis is an expansion of the recent head-to-head model proposed based on the polymerization of the 1-PI disulfide-linked dimer.
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