The solution structure of human β2-microglobulin reveals the prodromes of its amyloid transition

Giuliana Verdone, Alessandra Corazza, Paolo Viglino, Fabio Pettirossi, Sofia Giorgetti, Palma Mangione, Alessia Andreola, Monica Stoppini, Vittorio Bellotti, Gennaro Esposito

Research output: Contribution to journalArticle

Abstract

The solution structure of human β2-microglobulin (β2-m), the nonpolymorphic component of class I major histocompatibility complex (MHC-I), was determined by 1H 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 Cu2+ 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.

Original languageEnglish (US)
Pages (from-to)487-499
Number of pages13
JournalProtein Science
Volume11
Issue number3
DOIs
StatePublished - Mar 6 2002

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Solvation
Major Histocompatibility Complex
Amyloid
Surface charge
Ionic strength
Nuclear magnetic resonance spectroscopy
Secondary Protein Structure
Proteins
Crystal structure
Polymerization
Nuclear magnetic resonance
Osmolar Concentration
Molecules
Fibers
Magnetic Resonance Spectroscopy

Keywords

  • β2-microglobulin
  • Amyloid
  • Dialysis-related amyloidosis
  • NMR of proteins
  • Protein structure
  • Unfolding

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology

Cite this

Verdone, G., Corazza, A., Viglino, P., Pettirossi, F., Giorgetti, S., Mangione, P., ... Esposito, G. (2002). The solution structure of human β2-microglobulin reveals the prodromes of its amyloid transition. Protein Science, 11(3), 487-499. https://doi.org/10.1110/ps.29002

The solution structure of human β2-microglobulin reveals the prodromes of its amyloid transition. / Verdone, Giuliana; Corazza, Alessandra; Viglino, Paolo; Pettirossi, Fabio; Giorgetti, Sofia; Mangione, Palma; Andreola, Alessia; Stoppini, Monica; Bellotti, Vittorio; Esposito, Gennaro.

In: Protein Science, Vol. 11, No. 3, 06.03.2002, p. 487-499.

Research output: Contribution to journalArticle

Verdone, G, Corazza, A, Viglino, P, Pettirossi, F, Giorgetti, S, Mangione, P, Andreola, A, Stoppini, M, Bellotti, V & Esposito, G 2002, 'The solution structure of human β2-microglobulin reveals the prodromes of its amyloid transition', Protein Science, vol. 11, no. 3, pp. 487-499. https://doi.org/10.1110/ps.29002
Verdone G, Corazza A, Viglino P, Pettirossi F, Giorgetti S, Mangione P et al. The solution structure of human β2-microglobulin reveals the prodromes of its amyloid transition. Protein Science. 2002 Mar 6;11(3):487-499. https://doi.org/10.1110/ps.29002
Verdone, Giuliana ; Corazza, Alessandra ; Viglino, Paolo ; Pettirossi, Fabio ; Giorgetti, Sofia ; Mangione, Palma ; Andreola, Alessia ; Stoppini, Monica ; Bellotti, Vittorio ; Esposito, Gennaro. / The solution structure of human β2-microglobulin reveals the prodromes of its amyloid transition. In: Protein Science. 2002 ; Vol. 11, No. 3. pp. 487-499.
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