LOW-RESOLUTION X-RAY STRUCTURE OF HUMAN METHYLAMINE-TREATED ALPHA(2)-MACROGLOBULIN

The structure of methylamine-treated human alpha(2)-macroglobulin (alpha(2)M-MA), a 720-kDa tetrameric inactivated proteinase inhibitor from plasma, has been determined to a resolution of 10 Angstrom. Data were collected with synchrotron radiation at 120 K, and phases were calculated by multiple isomorphous replacement and solvent flattening. A novel feature of the structure of alpha(2)M is present in its proteinase-binding cavity, dividing it into two compartments. The potential sites for proteinase entrap ment in these compartments are sterically restricted. The positions of the thiol groups appearing from the functional important thiol esters upon their cleavage have been determined. They are found at the walls of the compartments at the center of the structure. The overall structure of alpha(2)M-MA is much more sphere-like than previously inferred from electron microscopy studies. However, several aspects of the structure are well described by recent three-dimensional reconstructions. Possible models for the monomer, the disulfide bridged dimer, and native alpha(2)M are discussed.