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Updated: Jul 6, 2026
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Interactions with and Membrane Permeabilization of Brain Mitochondria by Amyloid Fibrils
Published on: September 28, 2019
Altered dimer interface decreases stability in an amyloidogenic protein.
Elizabeth M Baden1, Barbara A L Owen, Francis C Peterson
1Department of Biochemistry and Molecular Biology, College of Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA.
The Journal of Biological Chemistry
|April 11, 2008
Summary
Structural changes in immunoglobulin light chain amyloidosis proteins reveal altered dimer interfaces, leading to faster amyloid fibril formation. Understanding these mechanisms may guide new drug design for incurable amyloid diseases.
Area of Science:
- Biochemistry
- Structural Biology
- Molecular Medicine
Background:
- Amyloidoses are incurable diseases characterized by amyloid formation, leading to cellular and organ damage.
- The precise molecular mechanisms driving amyloidogenesis remain poorly understood.
- Immunoglobulin light chain amyloidosis arises from the deposition of abnormal light chains produced by clonal plasma cells.
Purpose of the Study:
- To investigate the structural basis of immunoglobulin light chain amyloidosis.
- To compare the structure and stability of an amyloidogenic light chain (AL-09) with its wild-type counterpart (kappaI O18/O8).
Main Methods:
- X-ray crystallography was employed to determine the structures of AL-09 and kappaI O18/O8.
- Comparative analysis of dimer interfaces and protein stability was performed.
- In vitro amyloid fibril formation assays were conducted.
Main Results:
- Both AL-09 and kappaI O18/O8 proteins form dimers, but AL-09 exhibits a significantly altered dimer interface.
- Three non-conservative mutations in AL-09 are located at the dimer interface, correlating with decreased protein stability.
- AL-09 demonstrates accelerated amyloid fibril formation in vitro compared to the wild-type protein.
Conclusions:
- Altered dimer interfaces and decreased protein stability in AL-09 contribute to its rapid amyloidogenesis.
- Increased monomer stability and delayed fibril formation, alongside a proper dimer structure, may confer protection against amyloid diseases.
- These findings offer a potential new avenue for rational drug design targeting amyloidogenic proteins.
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Amyloid deposits were observed as early as 1639 in the liver and the spleen. In 1854, Rudolph Virchow performed iodine staining, normally used to...
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Amyloid deposits were observed as early as 1639 in the liver and the spleen. In 1854, Rudolph Virchow performed iodine staining, normally used to...
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