The solution structure of human beta2-microglobulin reveals the prodromes of its amyloid transition.
The solution structure of human beta2-microglobulin (beta2-m), the nonpolymorphic component of class I major histocompatibility complex (MHC-I), was determined by (1)H NMR spectroscopy and restrained modeling calculations. Compared to previous structural data obtained from the NMR secondary structure of the isolated protein and the crystal structure of MHC-I, in which the protein is associated to the heavy-chain component, several differences are observed. The most important rearrangements were observed for (1) strands V and VI (loss of the C-terminal and N-terminal end, respectively), (2) interstrand loop V-VI, and (3) strand I, including the N-terminal segment (displacement outward of the molecular core). These modifications can be considered as the prodromes of the amyloid transition. Solvation of the protected regions in MHC-I decreases the tertiary packing by breaking the contiguity of the surface hydrophobic patches at the interface with heavy chain and the nearby region at the surface charge cluster of the C-terminal segment. As a result, the molecule is placed in a state in which even minor charge and solvation changes in response to pH or ionic-strength variations can easily compromise the hydrophobic/hydrophilic balance and trigger the transition into a partially unfolded intermediate that starts with unpairing of strand I and leads to polymerization and precipitation into fibrils or amorphous aggregates. The same mechanism accounts for the partial unfolding and fiber formation subsequent to Cu(2+) binding, which is shown to occur primarily at His 31 and involve partially also His 13, the next available His residue along the partial unfolding pathway.
Verdone
Giuliana
G
Dipartimento di Scienze e Tecnologie Biomediche, Università di Udine, P.le Kolbe 4, 33100 Udine, Italy.
Corazza
Alessandra
A
Viglino
Paolo
P
Pettirossi
Fabio
F
Giorgetti
Sofia
S
Mangione
Palma
P
Andreola
Alessia
A
Stoppini
Monica
M
Bellotti
Vittorio
V
Esposito
Gennaro
G
D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D012996:Solutions; D001613:beta 2-Microglobulin / Q000737:chemistry*
D000682:Amyloid; D012996:Solutions; D001613:beta 2-Microglobulin