期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 289, 期 40, 页码 27513-27525出版社
ELSEVIER
DOI: 10.1074/jbc.M114.585638
关键词
Amyloid; Antibody; Multiple Myeloma; Protein Aggregation; X-ray Crystallography; Bence-Jones Proteins; Light Chain Amyloidosis; Light Chain Variable Domains; Systemic Amyloidosis
资金
- National Institutes of Health [AG-029430]
- National Science Foundation [MCB-0958111]
- Amyloidosis Foundation
- Direct For Biological Sciences [0958111] Funding Source: National Science Foundation
- Div Of Molecular and Cellular Bioscience [0958111] Funding Source: National Science Foundation
Background: Amyloid fibers are protein aggregates associated with numerous pathologies. Results: Mcg light chain variable domains form amyloid fibers through monomers. Conclusion: This light chain variable domain monomer is the fundamental unit required to form amyloid fibers. Significance: Understanding the molecular mechanism of Mcg light chain amyloid fiber formation has implications for treating systemic amyloidosis. Systemic light chain amyloidosis is a lethal disease characterized by excess immunoglobulin light chains and light chain fragments composed of variable domains, which aggregate into amyloid fibers. These fibers accumulate and damage organs. Some light chains induce formation of amyloid fibers, whereas others do not, making it unclear what distinguishes amyloid formers from non-formers. One mechanism by which sequence variation may reduce propensity to form amyloid fibers is by shifting the equilibrium toward an amyloid-resistant quaternary structure. Here we identify the monomeric form of the Mcg immunoglobulin light chain variable domain as the quaternary unit required for amyloid fiber assembly. Dimers of Mcg variable domains remain stable and soluble, yet become prone to assemble into amyloid fibers upon disassociation into monomers.
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