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Article Dans Une Revue Nature Communications Année : 2018

Conformational dynamics in crystals reveal the molecular bases for D76N beta-2 microglobulin aggregation propensity

Nicola Salvi
Martin Blackledge

Résumé

Spontaneous aggregation of folded and soluble native proteins in vivo is still a poorly understood process. A prototypic example is the D76N mutant of beta-2 microglobulin (beta 2m) that displays an aggressive aggregation propensity. Here we investigate the dynamics of beta 2m by X-ray crystallography, solid-state NMR, and molecular dynamics simulations to unveil the effects of the D76N mutation. Taken together, our data highlight the presence of minor disordered substates in crystalline beta 2m. The destabilization of the outer strands of D76N beta 2m accounts for the increased aggregation propensity. Furthermore, the computational modeling reveals a network of interactions with residue D76 as a keystone: this model allows predicting the stability of several point mutants. Overall, our study shows how the study of intrinsic dynamics in crystallo can provide crucial answers on protein stability and aggregation propensity. The comprehensive approach here presented may well be suited for the study of other folded amyloidogenic proteins.
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Dates et versions

hal-01859528 , version 1 (23-10-2020)

Identifiants

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Tanguy Le Marchand, Matteo de Rosa, Nicola Salvi, Benedetta Maria Sala, Loren B Andreas, et al.. Conformational dynamics in crystals reveal the molecular bases for D76N beta-2 microglobulin aggregation propensity. Nature Communications, 2018, 9, pp.1658-1-1658-11. ⟨10.1038/s41467-018-04078-y⟩. ⟨hal-01859528⟩
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