Three-Dimensional Structure of the Human Plasmin α 2-Macroglobulin Complex

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The three-dimensional reconstructions of the human plasmin α 2-macroglobulin binary complex were computed from electron microscopy images of stain and frozen-hydrated specimens. The structures show excellent agreement and reveal a molecule with approximate dimensions of 170 (length) × 140 (width) × 140 Å (depth). The asymmetric plasmin structure imparts significant asymmetry to the plasmin α 2-macroglobulin complex not seen in the structures resulting from the reaction of α 2-macroglobulin with methylamine or chymotrypsin. The structure shows, when combined with other studies, that the C-terminal catalytic domain of the rod-shaped plasmin molecule is entrapped inside of the α 2-macroglobulin cavity, whereas its N-terminal kringle domains protrude outside one end between the two arm-like features of the transformed α 2-macroglobulin structure. This arrangement ensures that the catalytic site of plasmin is prevented from degrading plasma proteins. The internalized C-terminal portion of the plasmin structure resides primarily on the major axis of α 2-macroglobulin, suggesting that after the initial cleavage of the two bait domains and the thiol esters, the rod-shaped plasmin molecule enters the α 2-macroglobulin cavity through the large openings afforded by the half-transformed structure. This mode of entrapment requires the untwisting and the separation of the two strands that constitute the α 2-macroglobulin structure.