Solution structure of beta(2)-microglobulin and insights into fibrillogenesis.
The solution structure of human beta(2)-microglobulin (beta(2)-m) was determined by (1)H NMR spectroscopy and restrained modeling calculations. Compared to the crystal structure of type I major histocompatibility complex (MHC-I), where the protein is associated to the heavy-chain component, several differences are observed, i.e., increased separation between strands A and B, displacements of strand C' and loop DE, shortening of strands D and E. These modifications can be considered as the prodromes of the amyloid transition. Even minor charge changes in response to pH, as is the case with H31 imidazole protonation, trigger the transition that starts with unpairing of strand A. The same mechanism accounts for the partial unfolding and fiber formation subsequent to Cu(2+) binding which is shown to occur primarily at H31. Solvation of the protected regions in MHC-I decreases the tertiary packing by breaking the contiguity of the surface hydrophobic patches via surface charge cluster. Mutants or truncated forms of beta(2)-m can be designed to remove the instability from H31 titration or to enhance the instability through surface charge suppression. By monitoring the conformational evolution of wild-type protein and variants thereof, either in response or absence of external perturbation, valuable insights into intermediate structure and fibrillogenesis mechanisms are gained.
Esposito
Gennaro
G
Dipartimento di Scienze e Tecnologie Biomediche, Università di Udine-P.le Kolbe, 4-33100 Udine, Italy. gesposito@mail.dstb.uniud.it
Corazza
Alessandra
A
Viglino
Paolo
P
Verdone
Giuliana
G
Pettirossi
Fabio
F
Fogolari
Federico
F
Makek
Ads
A
Giorgetti
Sofia
S
Mangione
Palma
P
Stoppini
Monica
M
Bellotti
Vittorio
V
D000682:Amyloid / Q000737:chemistry*; D018360:Crystallography, X-Ray; D004355:Drug Stability; D019143:Evolution, Molecular; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D019906:Nuclear Magnetic Resonance, Biomolecular; D011487:Protein Conformation; D012996:Solutions; D013816:Thermodynamics; D001613:beta 2-Microglobulin / Q000737:chemistry* / Q000235:genetics
D000682:Amyloid; D012996:Solutions; D001613:beta 2-Microglobulin