Biochemical and biophysical comparison of human and mouse beta-2 microglobulin reveals the molecular determinants of low amyloid propensity.
amyloid
crystal structure
molecular dynamics
protein aggregation
structural biology
Journal
The FEBS journal
ISSN: 1742-4658
Titre abrégé: FEBS J
Pays: England
ID NLM: 101229646
Informations de publication
Date de publication:
02 2020
02 2020
Historique:
received:
16
01
2019
revised:
09
07
2019
accepted:
15
08
2019
pubmed:
20
8
2019
medline:
21
10
2020
entrez:
18
8
2019
Statut:
ppublish
Résumé
The molecular bases of amyloid aggregation propensity are still poorly understood, especially for proteins that display a stable folded native structure. A prototypic example is human beta-2 microglobulin (β2m), which, when accumulated in patients, gives rise to dialysis-related amyloidosis. Interestingly, although the physiologic concentration of β2m in mice is five times higher than that found in human patients, no amyloid deposits are observed in mice. Moreover, murine β2m (mβ2m) not only displays a lower amyloid propensity both in vivo and in vitro but also inhibits the aggregation of human β2m in vitro. Here, we compared human and mβ2m for their aggregation propensity, ability to form soluble oligomers, stability, three-dimensional structure and dynamics. Our results indicate that mβ2m low-aggregation propensity is due to two concomitant aspects: the low-aggregation propensity of its primary sequence combined with the absence of high-energy amyloid-competent conformations under native conditions. The identification of the specific properties determining the low-aggregation propensity of mouse β2m will help delineate the molecular risk factors which cause a folded protein to aggregate.
Substances chimiques
Amyloid
0
beta 2-Microglobulin
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
546-560Informations de copyright
© 2019 Federation of European Biochemical Societies.
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