Download MendeleyCrystal structure of monomeric human beta-2-microglobulin reveals clues to its amyloidogenic properties.
Trinh, C.H., Smith, D.P., Kalverda, A.P., Phillips, S.E., Radford, S.E.(2002) Proc Natl Acad Sci U S A 99: 9771-9776
- PubMed: 12119416
- DOI: https://doi.org/10.1073/pnas.152337399
- Primary Citation of Related Structures:
1LDS - PubMed Abstract:
Dissociation of human beta-2-microglobulin (beta(2)m) from the heavy chain of the class I HLA complex is a critical first step in the formation of amyloid fibrils from this protein. As a consequence of renal failure, the concentration of circulating monomeric beta(2)m increases, ultimately leading to deposition of the protein into amyloid fibrils and development of the disorder, dialysis-related amyloidosis. Here we present the crystal structure of a monomeric form of human beta(2)m determined at 1.8-A resolution that reveals remarkable structural changes relative to the HLA-bound protein. These involve the restructuring of a beta bulge that separates two short beta strands to form a new six-residue beta strand at one edge of this beta sandwich protein. These structural changes remove key features proposed to have evolved to protect beta sheet proteins from aggregation [Richardson, J. & Richardson, D. (2002) Proc. Natl. Acad. Sci. USA 99, 2754-2759] and replaces them with an aggregation-competent surface. In combination with solution studies using (1)H NMR, we show that the crystal structure presented here represents a rare species in solution that could provide important clues about the mechanism of amyloid formation from the normally highly soluble native protein.
Organizational Affiliation:
Astbury Centre for Structural Molecular Biology, School of Biochemistry and Molecular Biology, University of Leeds, Leeds LS2 9JT, United Kingdom.
