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beta2-microglobulin H31Y variant 3D structure highlights the protein natural propensity towards intermolecular aggregation.

Rosano C, Zuccotti S, Mangione P, Giorgetti S, Bellotti V, Pettirossi F, Corazza A, Viglino P, Esposito G, Bolognesi M
J Mol Biol 335 1051-64 (2004)
Cited: 22 times
EuropePMC logo PMID: 14698299

Abstract

beta2-Microglobulin (beta2m) is the non-covalently bound light chain of the human class I major histocompatibility complex (MHC-I). The natural turnover of MHC-I gives rise to the release of beta2m into plasmatic fluids and to its catabolism in the kidney. beta2m dissociation from the heavy chain of the complex is a severe complication in patients receiving prolonged hemodialysis. As a consequence of renal failure, the increasing beta2m concentrations can lead to deposition of the protein as amyloid fibrils. Here we characterize the His31-->Tyr human beta2m mutant, a non-natural form of beta2m that is more stable than the wild-type protein, displaying a ten-fold acceleration of the slow phase of folding. We report the 2.9A resolution crystal structure and the NMR characterization of the mutant beta2m, focussing on selected structural features and on the molecular packing observed in the crystals. Juxtaposition of the four mutant beta2m molecules contained in the crystal asymmetric unit, and specific hydrogen bonds, stabilize a compact protein assembly. Conformational heterogeneity of the four independent molecules, some of their mutual interactions and partial unpairing of the N-terminal beta-strand in one protomer are in keeping with the amyloidogenic properties displayed by the mutant beta2m.

Reviews - 1py4 mentioned but not cited (1)

  1. Understanding the complex mechanisms of β2-microglobulin amyloid assembly. Eichner T, Radford SE. FEBS J 278 3868-3883 (2011)

Articles - 1py4 mentioned but not cited (2)

  1. Automated minimization of steric clashes in protein structures. Ramachandran S, Kota P, Ding F, Dokholyan NV. Proteins 79 261-270 (2011)
  2. A semiempirical method optimized for modeling proteins. Stewart JJP, Stewart AC. J Mol Model 29 284 (2023)


Reviews citing this publication (2)

  1. beta(2)-microglobulin: from physiology to amyloidosis. Heegaard NH. Amyloid 16 151-173 (2009)
  2. The Early Phase of β2-Microglobulin Aggregation: Perspectives From Molecular Simulations. Loureiro RJS, Faísca PFN. Front Mol Biosci 7 578433 (2020)

Articles citing this publication (17)

  1. Neurotoxic protein oligomers--what you see is not always what you get. Bitan G, Fradinger EA, Spring SM, Teplow DB. Amyloid 12 88-95 (2005)
  2. A native to amyloidogenic transition regulated by a backbone trigger. Eakin CM, Berman AJ, Miranker AD. Nat Struct Mol Biol 13 202-208 (2006)
  3. Conformational conversion during amyloid formation at atomic resolution. Eichner T, Kalverda AP, Thompson GS, Homans SW, Radford SE. Mol Cell 41 161-172 (2011)
  4. A regulatable switch mediates self-association in an immunoglobulin fold. Calabrese MF, Eakin CM, Wang JM, Miranker AD. Nat Struct Mol Biol 15 965-971 (2008)
  5. Magic angle spinning NMR analysis of beta2-microglobulin amyloid fibrils in two distinct morphologies. Debelouchina GT, Platt GW, Bayro MJ, Radford SE, Griffin RG. J Am Chem Soc 132 10414-10423 (2010)
  6. Nuclear magnetic resonance characterization of the refolding intermediate of beta2-microglobulin trapped by non-native prolyl peptide bond. Kameda A, Hoshino M, Higurashi T, Takahashi S, Naiki H, Goto Y. J Mol Biol 348 383-397 (2005)
  7. The controlling roles of Trp60 and Trp95 in beta2-microglobulin function, folding and amyloid aggregation properties. Esposito G, Ricagno S, Corazza A, Rennella E, Gümral D, Mimmi MC, Betto E, Pucillo CE, Fogolari F, Viglino P, Raimondi S, Giorgetti S, Bolognesi B, Merlini G, Stoppini M, Bolognesi M, Bellotti V. J Mol Biol 378 887-897 (2008)
  8. Beta2-microglobulin isoforms display an heterogeneous affinity for type I collagen. Giorgetti S, Rossi A, Mangione P, Raimondi S, Marini S, Stoppini M, Corazza A, Viglino P, Esposito G, Cetta G, Merlini G, Bellotti V. Protein Sci 14 696-702 (2005)
  9. DE-loop mutations affect beta2 microglobulin stability, oligomerization, and the low-pH unfolded form. Santambrogio C, Ricagno S, Colombo M, Barbiroli A, Bonomi F, Bellotti V, Bolognesi M, Grandori R. Protein Sci 19 1386-1394 (2010)
  10. Micro-heterogeneity and aggregation in beta2-microglobulin solutions: effects of temperature, pH, and conformational variant addition. Piazza R, Pierno M, Iacopini S, Mangione P, Esposito G, Bellotti V. Eur Biophys J 35 439-445 (2006)
  11. A recurrent D-strand association interface is observed in β-2 microglobulin oligomers. Colombo M, de Rosa M, Bellotti V, Ricagno S, Bolognesi M. FEBS J 279 1131-1143 (2012)
  12. Association of thin filaments into thick filaments revealing the structural hierarchy of amyloid fibrils. Kanno T, Yamaguchi K, Naiki H, Goto Y, Kawai T. J Struct Biol 149 213-218 (2005)
  13. Comment An accidental breach of a protein's natural defenses. Dobson CM. Nat Struct Mol Biol 13 295-297 (2006)
  14. Characterization of β2-microglobulin conformational intermediates associated to different fibrillation conditions. Santambrogio C, Ricagno S, Sobott F, Colombo M, Bolognesi M, Grandori R. J Mass Spectrom 46 734-741 (2011)
  15. Molecular characterization and expression analysis of beta2-microglobulin in large yellow croaker Pseudosciaena crocea. Yu S, Chen X, Ao J. Mol Biol Rep 36 1715-1723 (2009)
  16. Morphology and mechanical properties of multi-stranded amyloid fibrils probed by atomistic and coarse-grained simulations. Yoon G, Lee M, Kim K, Kim JI, Chang HJ, Baek I, Eom K, Na S. Phys Biol 12 066021 (2015)
  17. The Early Phase of β2m Aggregation: An Integrative Computational Study Framed on the D76N Mutant and the ΔN6 Variant. J S Loureiro R, Vila-Viçosa D, Machuqueiro M, Shakhnovich EI, F N Faísca P. Biomolecules 9 E366 (2019)


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