 |
PDBsum entry 1lds
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Immune system
|
PDB id
|
|
|
|
1lds
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
Contents |
 |
|
|
|
|
|
|
|
|
|
|
|
|
* Residue conservation analysis
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Crystal structure of monomeric human beta-2-Microglobulin reveals clues to its amyloidogenic properties.
|
|
|
Authors
|
|
C.H.Trinh,
D.P.Smith,
A.P.Kalverda,
S.E.Phillips,
S.E.Radford.
|
|
|
Ref.
|
|
Proc Natl Acad Sci U S A, 2002,
99,
9771-9776.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
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)
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.
|
|
|
|
|
|
|
|
Figure 1.
Fig. 1. Ribbon diagram of the crystal structures of (a)
M[H]  [2]m and (c)
HLA [2]m.
Detailed views of the conformation of residues 49-68 are also
shown for (b) M[H] [2]m and (d)
HLA [2]m. The
structure of HLA [2]m was
taken from PDB ID code 1DUZ (25). Individual strands are
labeled A although G. a and c were drawn by using the program
MOLSCRIPT (37) and RASTER 3D (38) and b and d, by using SPOCK
(39).
|
|
Figure 3.
Fig. 3. Schematic diagram showing the pattern of NH-NH
and C  H-C H NOEs
predicted for conformations of M[H] [2]m (a)
lacking and (b) containing the bulge
involving residues 53 and 54. C H-C H region
(c) and NH-NH region (d) of a 1H-1H NOESY spectrum of M[H] [2]m
acquired at pH 5.7, 37°C, in D[2]O and H[2]O, respectively.
Crosspeaks consistent with the presence of the bulge in
solution are marked in bold and underlined. Crosspeaks expected
were M[H] [2]m to
adopt a conformation in solution identical to that in a are
shown as solid circles.
|
|
|
|
|
|
|
|
|
|
