PDBsum entry 1lds

Immune system

PDB id: 1lds

Contents

Protein chain

97 a.a. *

Metals

_NA

Waters ×103

* Residue conservation analysis

PDB id:

1lds

Name:

Immune system

Title:

Crystal structure of monomeric human beta-2-microglobulin

Structure:

Beta-2-microglobulin. Chain: a. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: b2m. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.

Biol. unit:

Dimer (from PQS)

Resolution:

1.80Å R-factor: 0.187 R-free: 0.233

Authors:

C.H.Trinh,D.P.Smith,A.P.Kalverda,S.E.V.Phillips,S.E.Radford

Key ref:

C.H.Trinh et al. (2002). Crystal structure of monomeric human beta-2-microglobulin reveals clues to its amyloidogenic properties. Proc Natl Acad Sci U S A, 99, 9771-9776. PubMed id: 12119416 DOI: 10.1073/pnas.152337399

Date:

09-Apr-02 Release date: 31-Jul-02

Protein chain

P61769  (B2MG_HUMAN) -  Beta-2-microglobulin from Homo sapiens

Seq: 119 a.a.

Struc: 97 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

DOI no: 10.1073/pnas.152337399

Proc Natl Acad Sci U S A 99:9771-9776 (2002)

PubMed id: 12119416

Crystal structure of monomeric human beta-2-microglobulin reveals clues to its amyloidogenic properties.

C.H.Trinh, D.P.Smith, A.P.Kalverda, S.E.Phillips, S.E.Radford.

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.

Selected figure(s)

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.

Figures were selected by an automated process.