Solution structure of β2-microglobulin and insights into fibrillogenesis

Gennaro Esposito, Alessandra Corazza, Paolo Viglino, Giuliana Verdone, Fabio Pettirossi, Federico Fogolari, Ads Makek, Sofia Giorgetti, Palma Mangione, Monica Stoppini, Vittorio Bellotti

Research output: Contribution to journalArticle

Abstract

The solution structure of human β2-microglobulin (β2-m) was determined by 1H 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 Cu2+ 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 β2-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.

Original languageEnglish (US)
Pages (from-to)76-84
Number of pages9
JournalBiochimica et Biophysica Acta - Proteins and Proteomics
Volume1753
Issue number1
DOIs
StatePublished - Nov 10 2005

Fingerprint

Surface charge
Major Histocompatibility Complex
Protonation
Solvation
Titration
Amyloid
Nuclear magnetic resonance spectroscopy
Proteins
Magnetic Resonance Spectroscopy
Crystal structure
Fibers
Monitoring
imidazole
Proton Magnetic Resonance Spectroscopy

Keywords

  • β- microglobulin mutant
  • β- microglobulin NMR structure
  • β-microglobulin conformation
  • β-microglobulin solution structure
  • Amyloidogenic protein NMR
  • Protein NMR

ASJC Scopus subject areas

  • Analytical Chemistry
  • Biophysics
  • Biochemistry
  • Molecular Biology

Cite this

Solution structure of β2-microglobulin and insights into fibrillogenesis. / Esposito, Gennaro; Corazza, Alessandra; Viglino, Paolo; Verdone, Giuliana; Pettirossi, Fabio; Fogolari, Federico; Makek, Ads; Giorgetti, Sofia; Mangione, Palma; Stoppini, Monica; Bellotti, Vittorio.

In: Biochimica et Biophysica Acta - Proteins and Proteomics, Vol. 1753, No. 1, 10.11.2005, p. 76-84.

Research output: Contribution to journalArticle

Esposito, G, Corazza, A, Viglino, P, Verdone, G, Pettirossi, F, Fogolari, F, Makek, A, Giorgetti, S, Mangione, P, Stoppini, M & Bellotti, V 2005, 'Solution structure of β2-microglobulin and insights into fibrillogenesis', Biochimica et Biophysica Acta - Proteins and Proteomics, vol. 1753, no. 1, pp. 76-84. https://doi.org/10.1016/j.bbapap.2005.07.003
Esposito, Gennaro ; Corazza, Alessandra ; Viglino, Paolo ; Verdone, Giuliana ; Pettirossi, Fabio ; Fogolari, Federico ; Makek, Ads ; Giorgetti, Sofia ; Mangione, Palma ; Stoppini, Monica ; Bellotti, Vittorio. / Solution structure of β2-microglobulin and insights into fibrillogenesis. In: Biochimica et Biophysica Acta - Proteins and Proteomics. 2005 ; Vol. 1753, No. 1. pp. 76-84.
@article{b58211189d3c41e1870d44579a756012,
title = "Solution structure of β2-microglobulin and insights into fibrillogenesis",
abstract = "The solution structure of human β2-microglobulin (β2-m) was determined by 1H 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 Cu2+ 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 β2-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.",
keywords = "β- microglobulin mutant, β- microglobulin NMR structure, β-microglobulin conformation, β-microglobulin solution structure, Amyloidogenic protein NMR, Protein NMR",
author = "Gennaro Esposito and Alessandra Corazza and Paolo Viglino and Giuliana Verdone and Fabio Pettirossi and Federico Fogolari and Ads Makek and Sofia Giorgetti and Palma Mangione and Monica Stoppini and Vittorio Bellotti",
year = "2005",
month = "11",
day = "10",
doi = "10.1016/j.bbapap.2005.07.003",
language = "English (US)",
volume = "1753",
pages = "76--84",
journal = "Biochimica et Biophysica Acta - Proteins and Proteomics",
issn = "1570-9639",
publisher = "Elsevier",
number = "1",

}

TY - JOUR

T1 - Solution structure of β2-microglobulin and insights into fibrillogenesis

AU - Esposito, Gennaro

AU - Corazza, Alessandra

AU - Viglino, Paolo

AU - Verdone, Giuliana

AU - Pettirossi, Fabio

AU - Fogolari, Federico

AU - Makek, Ads

AU - Giorgetti, Sofia

AU - Mangione, Palma

AU - Stoppini, Monica

AU - Bellotti, Vittorio

PY - 2005/11/10

Y1 - 2005/11/10

N2 - The solution structure of human β2-microglobulin (β2-m) was determined by 1H 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 Cu2+ 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 β2-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.

AB - The solution structure of human β2-microglobulin (β2-m) was determined by 1H 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 Cu2+ 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 β2-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.

KW - β- microglobulin mutant

KW - β- microglobulin NMR structure

KW - β-microglobulin conformation

KW - β-microglobulin solution structure

KW - Amyloidogenic protein NMR

KW - Protein NMR

UR - http://www.scopus.com/inward/record.url?scp=27744552294&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=27744552294&partnerID=8YFLogxK

U2 - 10.1016/j.bbapap.2005.07.003

DO - 10.1016/j.bbapap.2005.07.003

M3 - Article

VL - 1753

SP - 76

EP - 84

JO - Biochimica et Biophysica Acta - Proteins and Proteomics

JF - Biochimica et Biophysica Acta - Proteins and Proteomics

SN - 1570-9639

IS - 1

ER -