4RMV

Crystal structure of the D76H Beta-2 Microglobulin mutant

Summary for 4RMV

• Entry DOI: 10.2210/pdb4rmv/pdb
• Related: 2YXF 4FXL 4RMQ 4RMR 4RMS 4RMT 4RMU 4RMW
• Descriptor: Beta-2-microglobulin, ACETATE ION, TRIETHYLENE GLYCOL, ... (4 entities in total)
• Functional Keywords: immunoglobin, beta-sandwitch, amyloidosis, pathologic mutation, genetic disease, mhc class i, immune system
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 12111.63

Authors

de Rosa, M.,Bolognesi, M.,Ricagno, S. (deposition date: 2014-10-22, release date: 2015-11-18, Last modification date: 2024-10-30)

Primary citation

Le Marchand, T.,de Rosa, M.,Salvi, N.,Sala, B.M.,Andreas, L.B.,Barbet-Massin, E.,Sormanni, P.,Barbiroli, A.,Porcari, R.,Sousa Mota, C.,de Sanctis, D.,Bolognesi, M.,Emsley, L.,Bellotti, V.,Blackledge, M.,Camilloni, C.,Pintacuda, G.,Ricagno, S.
Conformational dynamics in crystals reveal the molecular bases for D76N beta-2 microglobulin aggregation propensity.
Nat Commun, 9:1658-1658, 2018

PubMed 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.

PubMed: 29695721
DOI: 10.1038/s41467-018-04078-y

Experimental method

X-RAY DIFFRACTION (1.463 Å)