Human alpha(2)-macroglobulin is a tetrameric glycoprotein with a molecular
weight of 718 kDa that is present in human plasma at high concentrations. M
urine alpha(2)-macroglobulin is homologous to human alpha(2)-macroglobulin
but it undergoes posttranslational cleavage in the subunits. Each subunit o
f alpha(2)-macroglobulin contains a thiolester which can be cleaved by smal
l nucleophiles. In human alpha(2)-macroglobulin this results in a conformat
ional change to a receptor-recognized form and a change in the electrophore
tic mobility. Recent work has demonstrated that this process is reversible
and during this reversal nonproteolytic proteins can become covalently trap
ped within the human alpha(2)-macroglobulin molecule. The present study fur
ther investigates this observation and examines the question whether revers
al of thiolester cleavage occurs in mouse alpha(2)-macroglobulin. Previous
studies suggest that small nucleophiles only partially convert mouse alpha(
2)-macroglobulin to a receptor-recognized form. We demonstrate here that un
der appropriate conditions, mouse alpha(2)-macroglobulin is fully converted
by NH3. We also demonstrate that despite structural and kinetic difference
s between human and mouse alpha(2)-macroglobulin, both molecules are able t
o incorporate non-proteolytic ligands in a similar manner. This leads us to
propose a general model of ligand incorporation via nucleophilic exchange
in multimeric alpha-macroglobulins. (C) 1999 Elsevier Science B.V. All righ
ts reserved.