PDBsum entry 1uw3

Membrane protein

PDB id

1uw3

Contents

			Protein chain

					106 a.a. *

			Ligands

					GSH


					PO4

			Waters ×71

* Residue conservation analysis

References listed in PDB file

Key reference

Title

The crystal structure of the globular domain of sheep prion protein.

Authors

L.F.Haire, S.M.Whyte, N.Vasisht, A.C.Gill, C.Verma, E.J.Dodson, G.G.Dodson, P.M.Bayley.

Ref.

J Mol Biol, 2004, 336, 1175-1183. [DOI no: 10.1016/j.jmb.2003.12.059]

PubMed id

15037077

Abstract

The prion protein PrP is a naturally occurring polypeptide that becomes transformed from a normal conformation to that of an aggregated form, characteristic of pathological states in fatal transmissible spongiform conditions such as Creutzfeld-Jacob Disease and Bovine Spongiform Encephalopathy. We report the crystal structure, at 2 A resolution, of residues 123-230 of the C-terminal globular domain of the ARQ allele of sheep prion protein (PrP). The asymmetric unit contains a single molecule whose secondary structure and overall organisation correspond to those structures of PrPs from various mammalian species determined by NMR. The globular domain shows a close association of helix-1, the C-terminal portion of helix-2 and the N-terminal portion of helix-3, bounded by the intramolecular disulphide bond, 179-214. The loop 164-177, between beta2 and helix-2 is relatively well structured compared to the human PrP NMR structure. Analysis of the sheep PrP structure identifies two possible loci for the initiation of beta-sheet mediated polymerisation. One of these comprises the beta-strand, residues 129-131 that forms an intra-molecular beta-sheet with residues 161-163. This strand is involved in lattice contacts about a crystal dyad to generate a four-stranded intermolecular beta-sheet between neighbouring molecules. The second locus involves the region 188-204, which modelling suggests is able to undergo a partial alpha-->beta switch within the monomer. These loci provide sites within the PrPc monomer that could readily give rise to early intermediate species on the pathway to the formation of aggregated PrPSc containing additional intermolecular beta-structure.



	Figure 2. Figure 2. A, Portion of a CNS all omit map covering the vicinity of the phosphate ion linking the segment of the polypeptide at the immediate N terminus of helix-1 with the middle section of helix-3. (Liganding to Glu146 is not shown for clarity, see the text.) B, Schematic representation of the sheep PrP molecule. The helices, labelled H1-H3, are shown in blue, and the short segments of anti-parallel b-sheet are shown in red. C, Schematic representation of the helix-swapped dimer structure of the human prion protein.[6.] The bottom half of the dimer is in the same orientation as the sheep PrP shown in B and similarly coloured, but with H3 in light blue. The dyad-related monomer is at the top and its b-strands are coloured in green. The helices for the dyad-related molecule are distinguished by a prime. The exchange of H3 and H3' is accompanied by the formation of an additional segment of anti-parallel b-sheet, coloured in red and green (Figure drawn with Spock).		Figure 3. Figure 3. Comparison of the crystal structure of the globular domain of the ARQ allele of sheep PrP (blue) and the NMR structure of human PrP (yellow: 1hjm.pdb): least-squares superimposition of common residues, with an rms DIFFERENCE=1.73 Å for 100 C^a atoms. In addition to the three helices, the intramolecular b-sheet (arrows, b1:129-131; b2:161-163) is shown in red for sheep PrP, and grey for human PrP. The YYR epitope is at 162-164. The loop 164-174 between b2 and H2, is shown in green for sheep PrP. The three polymorphic residues of sheep (A133,R151,Q168), are shown in magenta (Figure drawn with Spock).

PROCHECK

	Headers