Abstract：
:The circulating protein transthyretin (TTR) can unfold, oligomerize, and form highly structured amyloid fibrils that are deposited in tissues, causing organ damage and disease. This pathogenic process is caused by a heritable TTR point mutation in cases of familial TTR-related amyloidosis or wild-type TTR in cases of age-associated amyloidosis (previously called senile systemic amyloidosis). The TTR amyloid cascade is hypothesized to begin with the dissociation of the TTR native tetrameric structure into folded but unstable monomeric TTR subunits. Unfolding of monomeric TTR initiates an oligomerization process leading to aggregation and fibril formation. Numerous proteostatic mechanisms for regulating the TTR amyloid cascade exist. Extracellular chaperones provide an innate defense against misfolded proteins. Clusterin (CLU), a plasma protein, has the capacity to recognize exposed hydrophobic regions of misfolded proteins, shielding them from aggregation. We have previously demonstrated that CLU is associated with the amyloid fibrils in cardiac tissues from patients with TTR amyloidosis. In this study, we have used tetrameric and monomeric TTR structural variants to determine the ability of CLU to inhibit TTR amyloid fibril formation. Using circular dichroism spectroscopy, we determined that CLU preferentially stabilizes monomeric TTR and generates increasingly stable conformations under acid stress. Moreover, studies using surface plasmon resonance showed a direct interaction of CLU with high-molecular weight TTR oligomers. The interactions of CLU with monomeric and aggregated TTR proceed in a cooperative manner in the presence of diflunisal, a small molecule drug used to stabilize TTR tetramers.
journal_name
Biochemistryjournal_title
Biochemistryauthors
Greene MJ,Klimtchuk ES,Seldin DC,Berk JL,Connors LHdoi
10.1021/bi5011249subject
Has Abstractpub_date
2015-01-20 00:00:00pages
268-78issue
2eissn
0006-2960issn
1520-4995journal_volume
54pub_type
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