Structure and activity of human clusterin.
type: CreativeWork
description: Clusterin is a heterodimeric disulfide linked glycoprotein secreted by many epithelia in adult and developing tissues. Clusterin is also induced in response to diverse injury or cell death stimuli. The protein interacts with, and is suggested to have, a relatively non specific affinity for markedly hydrophobic/amphipathic ligands including terminal complement components, Alzheimer's disease amyloid beta (Abeta) peptides, and apo AI-HDL in addition to immunoglobulins, TGFbeta receptors, heparin and the endocytic receptor LRP2. Little is known of clusterin structure and function. Sequences modeled as amphipathic alpha helices have been proposed as promiscous binding sites(s) for hydrophobic ligands. A reanalysis of these sequences using the COIL algorithm predicts a single conserved coiled-coil helix in each of the alpha and beta chains. These overlap, with heptads aligned, when each chain is aligned (antiparallel) with respect to the pattern of interchain disulfide bonds, and may reflect formation of an antiparallel coiled-coil with a cationic face that is proposed as an LRP2\heparin binding site. Distinct alpha and beta chain amphipathic helices encoded by exon 5 may constitute the hydrophobic ligand binding site. Partial proteolysis predominantly within or near these latter helices accompanies expression of human clusterin in Pichia pastoris and is associated with significant decreases in specific binding activity to IgG and Abeta 1-40 but not to LRP2 overexpressing differentiated F9 cells, in agreement with these binding site assignments. Although Zn+2 polymerized C9 (poly C9) and Abeta1-40 are mutual heterologous competitive clusterin-binding inhibitors, the specific binding of the recombinant protein to poly C9 is not as significantly diminished, suggesting a distinct but nearby binding site for this presumptive hydrophobic ligand. The C9 binding site is likely to be distinct from that of LRP2 since like IgG and Abeta 1-40 but unlike F9 cell surface binding poly…
abstract: Clusterin is a heterodimeric disulfide linked glycoprotein secreted by many epithelia in adult and developing tissues. Clusterin is also induced in response to diverse injury or cell death stimuli. The protein interacts with, and is suggested to have, a relatively non specific affinity for markedly hydrophobic/amphipathic ligands including terminal complement components, Alzheimer's disease amyloid beta (Abeta) peptides, and apo AI-HDL in addition to immunoglobulins, TGFbeta receptors, heparin and the endocytic receptor LRP2. Little is known of clusterin structure and function. Sequences modeled as amphipathic alpha helices have been proposed as promiscous binding sites(s) for hydrophobic ligands. A reanalysis of these sequences using the COIL algorithm predicts a single conserved coiled-coil helix in each of the alpha and beta chains. These overlap, with heptads aligned, when each chain is aligned (antiparallel) with respect to the pattern of interchain disulfide bonds, and may reflect formation of an antiparallel coiled-coil with a cationic face that is proposed as an LRP2\heparin binding site. Distinct alpha and beta chain amphipathic helices encoded by exon 5 may constitute the hydrophobic ligand binding site. Partial proteolysis predominantly within or near these latter helices accompanies expression of human clusterin in Pichia pastoris and is associated with significant decreases in specific binding activity to IgG and Abeta 1-40 but not to LRP2 overexpressing differentiated F9 cells, in agreement with these binding site assignments. Although Zn+2 polymerized C9 (poly C9) and Abeta1-40 are mutual heterologous competitive clusterin-binding inhibitors, the specific binding of the recombinant protein to poly C9 is not as significantly diminished, suggesting a distinct but nearby binding site for this presumptive hydrophobic ligand. The C9 binding site is likely to be distinct from that of LRP2 since like IgG and Abeta 1-40 but unlike F9 cell surface binding poly…
author: Lakins, Johnathon N.
keywords: Biology, Molecular.
identifier: Source: Dissertation Abstracts International, Volume: 61-01, Section: B, page: 0095.
date published: 2009-03-23T17:35:39Z
date modified: 2026-07-24T03:39:31Z
provider: University of Ottawa
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Ottawa (Canada)

PropertyValue
property ID: Handle
value: http://hdl.handle.net/10393/8699

PropertyValue
property ID: DOI
value: 10.20381/ruor-15948