Clusterin, a binding protein with a molten globule-like region

R. W. Bailey, A. K. Dunker, C. J. Brown, E. C. Garner, M. D. Griswold

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Abstract

Clusterin is a heterodimeric glycoprotein found in many tissues of the body and is the most abundant protein secreted by cultured rat Sertoli cells. The function of clusterin is unknown, but it has been associated with cellular injury, lipid transport, apoptosis, and it may be involved in the clearance of cellular debris caused by cell injury or death. Consistent with this last idea, clusterin has been shown to bind to a variety of molecules with high affinity including lipids, peptides, and proteins and the hydrophobic probe 1-anilino-8-naphthalenesulfonate (ANS). Given this variety of ligands, clusterin must have specific structural features that provide the protein with its promiscuous binding activity. Using sequence analyses, we show that clusterin likely contains three long regions of natively disordered or molten globule-like structures containing putative amphipathic α-helices. These disordered regions were highly sensitive to trypsin digestion, indicating a flexible nature. The effects of denaturation on the fluorescence of the clusterin-ANS complex were compared between proteins with structured binding pockets and molten globular forms of proteins. Clusterin bound ANS in a manner that was very similar to that of molten globular proteins. Furthermore, we found that, when bound to ANS, at least one cleavage site within the protease-sensitive disordered regions of clusterin was protected from trypsin digestion. In addition, we show that clusterin can function as a biological detergent that can solubilize bacteriorhodopsin. We propose that natively disordered regions with amphipathic helices form a dynamic, molten globule-like binding site and provide clusterin the ability to bind to a variety of molecules.

Original languageEnglish (US)
Pages (from-to)11828-11840
Number of pages13
JournalBiochemistry
Volume40
Issue number39
DOIs
StatePublished - Oct 2 2001

ASJC Scopus subject areas

  • Biochemistry

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    Bailey, R. W., Dunker, A. K., Brown, C. J., Garner, E. C., & Griswold, M. D. (2001). Clusterin, a binding protein with a molten globule-like region. Biochemistry, 40(39), 11828-11840. https://doi.org/10.1021/bi010135x