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PDBsum entry 5csg
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Immune system
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PDB id
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5csg
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References listed in PDB file
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Key reference
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Title
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Conformational dynamics in crystals reveal the molecular bases for d76n beta-2 microglobulin aggregation propensity.
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Authors
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T.Le marchand,
M.De rosa,
N.Salvi,
B.M.Sala,
L.B.Andreas,
E.Barbet-Massin,
P.Sormanni,
A.Barbiroli,
R.Porcari,
C.Sousa mota,
D.De sanctis,
M.Bolognesi,
L.Emsley,
V.Bellotti,
M.Blackledge,
C.Camilloni,
G.Pintacuda,
S.Ricagno.
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Ref.
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Nat Commun, 2018,
9,
1658.
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PubMed id
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Abstract
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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.
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