Incomplete Refolding of Antibody Light Chains to Non-Native, Protease-Sensitive Conformations Leads to Aggregation: A Mechanism of Amyloidogenesis in Patients?

ABSTRACT: Genetic, biochemical, and pharmacologic evidence supports the hypothesis that conformationally altered or misfolded protein states enable aggregation and cytotoxicity in the systemic amyloid diseases. Reversible structural fluctuations of natively folded proteins are involved in the aggregation of many degenerative disease associated proteins. Herein, we use antibody light chains (LCs) that form amyloid fibrils in AL amyloidosis to consider an alternative hypothesis of amyloidogenesis: that transient unfolding and incomplete extracellular refolding of secreted proteins can lead to metastable, alternatively folded states that are more susceptible to aggregation or to endoproteolysis that can release aggregation-prone fragments. Refolding of full-length λ6a LC dimers comprising an interchain

SUBMITTER: Morgan GJ 

PROVIDER: S-EPMC5736400 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature