Abstract
β2-Microglobulin (β2m) is the non-covalently bound light chain of the human class I major histocompatibility complex (MHC-I). The natural turnover of MHC-I gives rise to the release of β2m into plasmatic fluids and to its catabolism in the kidney. β2m dissociation from the heavy chain of the complex is a severe complication in patients receiving prolonged hemodialysis. As a consequence of renal failure, the increasing β2m concentrations can lead to deposition of the protein as amyloid fibrils. Here we characterize the His31→Tyr human β2m mutant, a non-natural form of β2m that is more stable than the wild-type protein, displaying a ten-fold acceleration of the slow phase of folding. We report the 2.9Å resolution crystal structure and the NMR characterization of the mutant β2m, focussing on selected structural features and on the molecular packing observed in the crystals. Juxtaposition of the four mutant β2m molecules contained in the crystal asymmetric unit, and specific hydrogen bonds, stabilize a compact protein assembly. Conformational heterogeneity of the four independent molecules, some of their mutual interactions and partial unpairing of the N-terminal β-strand in one protomer are in keeping with the amyloidogenic properties displayed by the mutant β2m.
| Original language | English |
|---|---|
| Pages (from-to) | 1051-1064 |
| Number of pages | 14 |
| Journal | Journal of Molecular Biology |
| Volume | 335 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - Jan 23 2004 |
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Keywords
- β2-microglobulin
- Amyloid aggregate
- NMR structure
- Protein structure
- X-ray crystallography
ASJC Scopus subject areas
- Virology
Cite this
β2-Microglobulin H31Y Variant 3D Structure Highlights the Protein Natural Propensity Towards Intermolecular Aggregation. / Rosano, C.; Zuccotti, S.; Mangione, P.; Giorgetti, S.; Bellotti, V.; Pettirossi, F.; Corazza, A.; Viglino, P.; Esposito, G.; Bolognesi, M.
In: Journal of Molecular Biology, Vol. 335, No. 4, 23.01.2004, p. 1051-1064.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - β2-Microglobulin H31Y Variant 3D Structure Highlights the Protein Natural Propensity Towards Intermolecular Aggregation
AU - Rosano, C.
AU - Zuccotti, S.
AU - Mangione, P.
AU - Giorgetti, S.
AU - Bellotti, V.
AU - Pettirossi, F.
AU - Corazza, A.
AU - Viglino, P.
AU - Esposito, G.
AU - Bolognesi, M.
PY - 2004/1/23
Y1 - 2004/1/23
N2 - β2-Microglobulin (β2m) is the non-covalently bound light chain of the human class I major histocompatibility complex (MHC-I). The natural turnover of MHC-I gives rise to the release of β2m into plasmatic fluids and to its catabolism in the kidney. β2m dissociation from the heavy chain of the complex is a severe complication in patients receiving prolonged hemodialysis. As a consequence of renal failure, the increasing β2m concentrations can lead to deposition of the protein as amyloid fibrils. Here we characterize the His31→Tyr human β2m mutant, a non-natural form of β2m that is more stable than the wild-type protein, displaying a ten-fold acceleration of the slow phase of folding. We report the 2.9Å resolution crystal structure and the NMR characterization of the mutant β2m, focussing on selected structural features and on the molecular packing observed in the crystals. Juxtaposition of the four mutant β2m molecules contained in the crystal asymmetric unit, and specific hydrogen bonds, stabilize a compact protein assembly. Conformational heterogeneity of the four independent molecules, some of their mutual interactions and partial unpairing of the N-terminal β-strand in one protomer are in keeping with the amyloidogenic properties displayed by the mutant β2m.
AB - β2-Microglobulin (β2m) is the non-covalently bound light chain of the human class I major histocompatibility complex (MHC-I). The natural turnover of MHC-I gives rise to the release of β2m into plasmatic fluids and to its catabolism in the kidney. β2m dissociation from the heavy chain of the complex is a severe complication in patients receiving prolonged hemodialysis. As a consequence of renal failure, the increasing β2m concentrations can lead to deposition of the protein as amyloid fibrils. Here we characterize the His31→Tyr human β2m mutant, a non-natural form of β2m that is more stable than the wild-type protein, displaying a ten-fold acceleration of the slow phase of folding. We report the 2.9Å resolution crystal structure and the NMR characterization of the mutant β2m, focussing on selected structural features and on the molecular packing observed in the crystals. Juxtaposition of the four mutant β2m molecules contained in the crystal asymmetric unit, and specific hydrogen bonds, stabilize a compact protein assembly. Conformational heterogeneity of the four independent molecules, some of their mutual interactions and partial unpairing of the N-terminal β-strand in one protomer are in keeping with the amyloidogenic properties displayed by the mutant β2m.
KW - β2-microglobulin
KW - Amyloid aggregate
KW - NMR structure
KW - Protein structure
KW - X-ray crystallography
UR - http://www.scopus.com/inward/record.url?scp=0346493042&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0346493042&partnerID=8YFLogxK
U2 - 10.1016/j.jmb.2003.11.040
DO - 10.1016/j.jmb.2003.11.040
M3 - Article
C2 - 14698299
AN - SCOPUS:0346493042
VL - 335
SP - 1051
EP - 1064
JO - Journal of Molecular Biology
JF - Journal of Molecular Biology
SN - 0022-2836
IS - 4
ER -