Pathogenic D76N Variant of β2-Microglobulin: Synergy of Diverse Effects in Both the Native and Amyloid States
| Autor: | Károly Liliom, Yuxi Lin, Éva Bulyáki, András Micsonai, Young-Ho Lee, Gabriella Gellén, József Kardos, Alexandra Papp, Tamás Molnár, Mihály Józsi, Masatomo So, Yuji Goto, Gitta Schlosser, Keiichi Yamaguchi, Attila István Kovács, Borbála Márialigeti, Judit Kun, Henrietta Vadászi |
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| Rok vydání: | 2021 |
| Předmět: |
amyloidosis
General Immunology and Microbiology Amyloid QH301-705.5 Beta-2 microglobulin β2-microglobulin Amyloidosis Point mutation CD spectroscopy Protein aggregation Biology medicine.disease Fibril General Biochemistry Genetics and Molecular Biology protein aggregation dialysis-related amyloidosis protein stability medicine Extracellular Native state Biophysics differential scanning calorimetry Biology (General) General Agricultural and Biological Sciences ion-pairs |
| Zdroj: | Biology, Vol 10, Iss 1197, p 1197 (2021) Biology Volume 10 Issue 11 |
| ISSN: | 2079-7737 |
| Popis: | β2-microglobulin (β2m), the light chain of the MHC-I complex, is associated with dialysis-related amyloidosis (DRA). Recently, a hereditary systemic amyloidosis was discovered, caused by a naturally occurring D76N β2m variant, which showed a structure remarkably similar to the wild-type (WT) protein, albeit with decreased thermodynamic stability and increased amyloidogenicity. Here, we investigated the role of the D76N mutation in the amyloid formation of β2m by point mutations affecting the Asp76-Lys41 ion-pair of WT β2m and the charge cluster on Asp38. Using a variety of biophysical techniques, we investigated the conformational stability and partial unfolding of the native state of the variants, as well as their amyloidogenic propensity and the stability of amyloid fibrils under various conditions. Furthermore, we studied the intermolecular interactions of WT and mutant proteins with various binding partners that might have in vivo relevance. We found that, relative to WT β2m, the exceptional amyloidogenicity of the pathogenic D76N β2m variant is realized by the deleterious synergy of diverse effects of destabilized native structure, higher sensitivity to negatively charged amphiphilic molecules (e.g., lipids) and polyphosphate, more effective fibril nucleation, higher conformational stability of fibrils, and elevated affinity for extracellular components, including extracellular matrix proteins. |
| Databáze: | OpenAIRE |
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