Clusterin is an ATP-independent chaperone with very broad substrate specificity that stabilizes stressed proteins in a folding-competent state

We recently reported that the ubiquitous, secreted protein clusterin has ch aperone activity in vitro [Humphreys et al. (1999) J. Biol. Chem. 274, 6875 -6881]. In this study, we demonstrate that clusterin (i) inhibits stress-in duced precipitation of a very broad range of structurally divergent protein substrates, (ii) binds irreversibly via an ATP-independent mechanism to st ressed proteins to form solubilized high molecular weight complexes, (iii) lacks detectable ATPase activity, (iv) when acting alone, does not effect r efolding of stressed proteins in vitro, and (v) stabilizes stressed protein s in a state competent for refolding by heat shock protein 70 (HSP70). Furt hermore, we show that, at physiological levels, clusterin inhibits stress-i nduced precipitation of proteins in undiluted human serum. Clusterin repres ents the first identified secreted mammalian chaperone. However, reports fr om others suggest that, at least under stress conditions, clusterin may be retained within cells to exert a protective effect. Regardless of the topol ogical site(s) of action, the demonstration that clusterin can stabilize st ressed proteins in a refolding-competent state suggests that, during stress es, the action of clusterin may inhibit rapid and irreversible protein prec ipitation and produce a reservoir of inactive but stabilized molecules from which other refolding chaperones can subsequently salvage functional prote ins.