The three-dimensional structure of the human α2-macroglobulin dimer reveals its structural organization in the tetrameric native and chymotrypsin α2-macroglobulin complexes

Abstract

Three-dimensional electron microscopy reconstructions of the human α2-macroglobulin (α2M) dimer and chymotrypsin-transformed α2M reveal the structural arrangement of the two dimers that comprise native and proteinase-transformed molecules. They consist of two side-by-side extended strands that have a clockwise and counterclockwise twist about their major axes in the native and transformed structures, respectively. This and other studies show that there are major contacts between the two strands at both ends of the molecule that evidently sequester the receptor binding domains. Upon proteinase cleavage of the bait domains and subsequent thiol ester cleavages, which occur near the central region of the molecule, the two strands separate by 40 Å at both ends of the structure to expose the receptor binding domains and form the arm-like extensions of the transformed α2M. During the transformation of the structure, the strands untwist to expose the α2M central cavity to the proteinase. This extraordinary change in the architecture of α2M functions to completely engulf two molecules of chymotrypsin within its central cavity and to irreversibly encapsulate them.