Pathogenic D76N Variant of β<sub>2</sub>-Microglobulin: Synergy of Diverse Effects in Both the Native and Amyloid States

β<sub>2</sub>-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...

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Autores principales:	Éva Bulyáki, Judit Kun, Tamás Molnár, Alexandra Papp, András Micsonai, Henrietta Vadászi, Borbála Márialigeti, Attila István Kovács, Gabriella Gellén, Keiichi Yamaguchi, Yuxi Lin, Masatomo So, Mihály Józsi, Gitta Schlosser, Young-Ho Lee, Károly Liliom, Yuji Goto, József Kardos
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	amyloidosis protein aggregation β<sub>2</sub>-microglobulin dialysis-related amyloidosis protein stability ion-pairs Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/dea39e0efe244054b9a06e94524de24d
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spelling	oai:doaj.org-article:dea39e0efe244054b9a06e94524de24d2021-11-25T16:47:54ZPathogenic D76N Variant of β<sub>2</sub>-Microglobulin: Synergy of Diverse Effects in Both the Native and Amyloid States10.3390/biology101111972079-7737https://doaj.org/article/dea39e0efe244054b9a06e94524de24d2021-11-01T00:00:00Zhttps://www.mdpi.com/2079-7737/10/11/1197https://doaj.org/toc/2079-7737β<sub>2</sub>-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.Éva BulyákiJudit KunTamás MolnárAlexandra PappAndrás MicsonaiHenrietta VadásziBorbála MárialigetiAttila István KovácsGabriella GellénKeiichi YamaguchiYuxi LinMasatomo SoMihály JózsiGitta SchlosserYoung-Ho LeeKároly LiliomYuji GotoJózsef KardosMDPI AGarticleamyloidosisprotein aggregationβ<sub>2</sub>-microglobulindialysis-related amyloidosisprotein stabilityion-pairsBiology (General)QH301-705.5ENBiology, Vol 10, Iss 1197, p 1197 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	amyloidosis protein aggregation β<sub>2</sub>-microglobulin dialysis-related amyloidosis protein stability ion-pairs Biology (General) QH301-705.5
spellingShingle	amyloidosis protein aggregation β<sub>2</sub>-microglobulin dialysis-related amyloidosis protein stability ion-pairs Biology (General) QH301-705.5 Éva Bulyáki Judit Kun Tamás Molnár Alexandra Papp András Micsonai Henrietta Vadászi Borbála Márialigeti Attila István Kovács Gabriella Gellén Keiichi Yamaguchi Yuxi Lin Masatomo So Mihály Józsi Gitta Schlosser Young-Ho Lee Károly Liliom Yuji Goto József Kardos Pathogenic D76N Variant of β<sub>2</sub>-Microglobulin: Synergy of Diverse Effects in Both the Native and Amyloid States
description	β<sub>2</sub>-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.
format	article
author	Éva Bulyáki Judit Kun Tamás Molnár Alexandra Papp András Micsonai Henrietta Vadászi Borbála Márialigeti Attila István Kovács Gabriella Gellén Keiichi Yamaguchi Yuxi Lin Masatomo So Mihály Józsi Gitta Schlosser Young-Ho Lee Károly Liliom Yuji Goto József Kardos
author_facet	Éva Bulyáki Judit Kun Tamás Molnár Alexandra Papp András Micsonai Henrietta Vadászi Borbála Márialigeti Attila István Kovács Gabriella Gellén Keiichi Yamaguchi Yuxi Lin Masatomo So Mihály Józsi Gitta Schlosser Young-Ho Lee Károly Liliom Yuji Goto József Kardos
author_sort	Éva Bulyáki
title	Pathogenic D76N Variant of β<sub>2</sub>-Microglobulin: Synergy of Diverse Effects in Both the Native and Amyloid States
title_short	Pathogenic D76N Variant of β<sub>2</sub>-Microglobulin: Synergy of Diverse Effects in Both the Native and Amyloid States
title_full	Pathogenic D76N Variant of β<sub>2</sub>-Microglobulin: Synergy of Diverse Effects in Both the Native and Amyloid States
title_fullStr	Pathogenic D76N Variant of β<sub>2</sub>-Microglobulin: Synergy of Diverse Effects in Both the Native and Amyloid States
title_full_unstemmed	Pathogenic D76N Variant of β<sub>2</sub>-Microglobulin: Synergy of Diverse Effects in Both the Native and Amyloid States
title_sort	pathogenic d76n variant of β<sub>2</sub>-microglobulin: synergy of diverse effects in both the native and amyloid states
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/dea39e0efe244054b9a06e94524de24d
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Pathogenic D76N Variant of β<sub>2</sub>-Microglobulin: Synergy of Diverse Effects in Both the Native and Amyloid States

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