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

Tanguy Le Marchand, Matteo de Rosa, Nicola Salvi, Benedetta Maria Sala, Loren B. Andreas, Emeline Barbet-Massin, Pietro Sormanni, Alberto Barbiroli, Riccardo Porcari, Cristiano Sousa Mota, Daniele de Sanctis, Martino Bolognesi, Lyndon Emsley, Vittorio Bellotti, Martin Blackledge, Carlo Camilloni (), Guido Pintacuda () and Stefano Ricagno ()
Additional contact information
Tanguy Le Marchand: Université de Lyon
Matteo de Rosa: Università degli Studi di Milano
Nicola Salvi: Institut de Biologie Structurale, CNRS, CEA, UGA
Benedetta Maria Sala: Università degli Studi di Milano
Loren B. Andreas: Université de Lyon
Emeline Barbet-Massin: Université de Lyon
Pietro Sormanni: University of Cambridge
Alberto Barbiroli: Università degli Studi di Milano
Riccardo Porcari: University College London
Cristiano Sousa Mota: ESRF - The European Synchrotron
Daniele de Sanctis: ESRF - The European Synchrotron
Martino Bolognesi: Università degli Studi di Milano
Lyndon Emsley: Université de Lyon
Vittorio Bellotti: University College London
Martin Blackledge: Institut de Biologie Structurale, CNRS, CEA, UGA
Carlo Camilloni: Università degli Studi di Milano
Guido Pintacuda: Université de Lyon
Stefano Ricagno: Università degli Studi di Milano

Nature Communications, 2018, vol. 9, issue 1, 1-11

Abstract: Abstract 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 (β2m) that displays an aggressive aggregation propensity. Here we investigate the dynamics of β2m 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 β2m. The destabilization of the outer strands of D76N β2m 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.

Date: 2018
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DOI: 10.1038/s41467-018-04078-y

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