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Properties of some variants of human beta2-microglobulin and amyloidogenesis

Alessandra Corazza1, Fabio Pettirossi, Paolo Viglino

  • 1Dipartimento di Scienze e Tecnologie Biomediche and Microgravity, Aging, Training, and Immobility, Centre of Excellence, Università di Udine, Piazzale Kolbe 4, 33100 Udine, Italy.

The Journal of Biological Chemistry
|December 9, 2003
PubMed

Insights

Three human beta(2)-microglobulin variants were studied. Two variants showed reduced stability, while one exhibited increased stability, impacting protein folding and precipitation kinetics in beta(2)-m fibrillogenesis.

Area of Science:

  • Biochemistry
  • Structural Biology
  • Protein Misfolding Diseases

Background:

  • Human beta(2)-microglobulin (beta(2)-m) is a component of the MHC class I molecule.
  • Beta(2)-m is implicated in amyloidosis, particularly in patients with chronic renal failure.
  • Understanding the structural and dynamic properties of beta(2)-m variants is crucial for elucidating amyloid formation mechanisms.

Purpose of the Study:

  • To investigate the stability and structural characteristics of three human beta(2)-m variants.
  • To compare the behavior of these variants with wild-type beta(2)-m.
  • To gain insights into the mechanism of beta(2)-m fibrillogenesis and amyloid transition.

Main Methods:

  • Protein expression and purification of wild-type and variant beta(2)-m.
  • (1)H NMR spectroscopy for structural determination.
  • Restrained modeling to analyze protein conformation.
  • Monitoring of protein precipitation and unfolding over time.

Main Results:

  • Two variants (R3Abeta(2)-m and DeltaN3beta(2)-m) displayed reduced unfolding free energy compared to wild-type beta(2)-m.
  • One variant (H31Ybeta(2)-m) exhibited increased stability.
  • All variants, and sometimes wild-type beta(2)-m, showed precipitation and unfolding within 4-6 weeks.
  • Protein loss followed pseudo-zeroth order kinetics, suggesting a nucleated conformational conversion mechanism for fibrillogenesis.

Conclusions:

  • Beta(2)-m fibrillogenesis likely proceeds via a nucleated conformational conversion scheme.
  • A nucleated oligomeric species is proposed as the stable intermediate in fibrillogenesis.
  • The monomeric intermediate is a necessary transition step from native protein to the nucleated oligomer.

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