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 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 murine β2m for their aggregation propensity, ability to form soluble oligomers, stability, three-dimensional structure and dynamics. Our results indicate that murine β2m 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.
Biochemical and biophysical comparison of human and mouse beta-2 microglobulin reveals the molecular determinants of low amyloid propensity / A. Achour, L. Broggini, X. Han, R. Sun, C. Santambrogio, J. Buratto, C. Visentin, A. Barbiroli, C.M.G. De Luca, P. Sormanni, F. Moda, A. De Simone, T. Sandalova, R. Grandori, C. Camilloni, S. Ricagno. - In: THE FEBS JOURNAL. - ISSN 1742-464X. - 287:3(2020), pp. 546-560.
|Titolo:||Biochemical and biophysical comparison of human and mouse beta-2 microglobulin reveals the molecular determinants of low amyloid propensity|
BROGGINI, LUCA (Secondo)
CAMILLONI, CARLO (Penultimo) (Corresponding)
RICAGNO, STEFANO (Ultimo) (Corresponding)
|Parole Chiave:||amyloid; crystal structure; molecular dynamics; protein aggregation; structural biology|
|Settore Scientifico Disciplinare:||Settore BIO/10 - Biochimica|
Settore FIS/07 - Fisica Applicata(Beni Culturali, Ambientali, Biol.e Medicin)
|Data di pubblicazione:||2020|
|Data ahead of print / Data di stampa:||2019|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1111/febs.15046|
|Appare nelle tipologie:||01 - Articolo su periodico|