Clusterin Is an ATP−Independent Chaperone with Very Broad Substrate Specificity that Stabilizes Stressed Proteins in a Folding-Competent State

Abstract

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

Clusterin as a biomarker in murine and human intestinal neoplasia

“…Although identified two decades ago, its functions have not yet been fully elucidated (14,34). Previous reports have correlated clusterin expression with cell responses to stress (35), cell damage recovery (36,37), senescence (38,39), tumorigenesis (14,40), and apoptosis (14). In this report, we have demonstrated that clusterin expression is relatively uniform despite the regional differences of intestinal tumors in average size, frequency, and morphology (9,24).…”

α2-Macroglobulin and Haptoglobin Suppress Amyloid Formation by Interacting with Prefibrillar Protein Species

“…These extracellular chaperones are also known to potently inhibit amorphous aggregation of proteins (10,11,35,38,39). We suggest that this small family of chaperones is likely to be an important part of a system that defends the human body against inappropriate extracellular protein aggregation, which can be either amorphous or amyloid in character.…”

Failure to complete apoptosis following neonatal hypoxia–ischemia manifests as “continuum” phenotype of cell death and occurs with multiple manifestations of mitochondrial dysfunction in rodent forebrain

“…Clusterin or apolipoprotein J is a molecular chaperone highly expressed in brain (Poon et al, 2000). Although, clusterin has been proposed as having a role in the regulation of apoptosis , in the neonatal brain clusterin accumulates in neurons dying with an excitotoxic phenotype following neonatal HI and appears to differentiate excitotoxic from caspase-dependent apoptosis (Han et al, 2001).…”