PDBsum entry 1tqb

Unknown function/immune system

PDB id: 1tqb

Contents

Protein chains

102 a.a. *

212 a.a. *

219 a.a. *

Waters ×57

* Residue conservation analysis

PDB id:

1tqb

Name:

Unknown function/immune system

Title:

Ovine recombinant prp(114-234), vrq variant in complex with the fab of the vrq14 antibody

Structure:

Prion protein. Chain: a. Fragment: vrq variant, residues 127-228. Synonym: ovprp. Engineered: yes. Vrq14 fab heavy chain. Chain: b. Fragment: vrq14 fab fragment. Engineered: yes.

Source:

Ovis aries. Sheep. Organism_taxid: 9940. Gene: prnp sheep vrq variant. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008. Mus musculus. House mouse. Organism_taxid: 10090.

Biol. unit:

Trimer (from PQS)

Resolution:

2.55Å R-factor: 0.214 R-free: 0.268

Authors:

F.Eghiaian,J.Grosclaude,P.Debey,B.Doublet,E.Treguer,H.Rezaei, M.Knossow

Key ref:

F.Eghiaian et al. (2004). Insight into the PrPC-->PrPSc conversion from the structures of antibody-bound ovine prion scrapie-susceptibility variants. Proc Natl Acad Sci U S A, 101, 10254-10259. PubMed id: 15240887 DOI: 10.1073/pnas.0400014101

Date:

17-Jun-04 Release date: 06-Jul-04

Protein chain

P23907  (PRIO_SHEEP) -  Major prion protein from Ovis aries

Seq: 256 a.a.

Struc: 102 a.a.*

Protein chain

No UniProt id for this chain

Struc: 212 a.a.

Protein chain

No UniProt id for this chain

Struc: 219 a.a.

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

DOI no: 10.1073/pnas.0400014101

Proc Natl Acad Sci U S A 101:10254-10259 (2004)

PubMed id: 15240887

Insight into the PrPC-->PrPSc conversion from the structures of antibody-bound ovine prion scrapie-susceptibility variants.

F.Eghiaian, J.Grosclaude, S.Lesceu, P.Debey, B.Doublet, E.Tréguer, H.Rezaei, M.Knossow.

ABSTRACT

Prion diseases are associated with the conversion of the alpha-helix rich prion protein (PrPC) into a beta-structure-rich insoluble conformer (PrPSc) that is thought to be infectious. The mechanism for the PrPC-->PrPSc conversion and its relationship with the pathological effects of prion diseases are poorly understood, partly because of our limited knowledge of the structure of PrPSc. In particular, the way in which mutations in the PRNP gene yield variants that confer different susceptibilities to disease needs to be clarified. We report here the 2.5-A-resolution crystal structures of three scrapie-susceptibility ovine PrP variants complexed with an antibody that binds to PrPC and to PrPSc; they identify two important features of the PrPC-->PrPSc conversion. First, the epitope of the antibody mainly consists of the last two turns of ovine PrP second alpha-helix. We show that this is a structural invariant in the PrPC-->PrPSc conversion; taken together with biochemical data, this leads to a model of the conformational change in which the two PrPC C-terminal alpha-helices are conserved in PrPSc, whereas secondary structure changes are located in the N-terminal alpha-helix. Second, comparison of the structures of scrapie-sensitivity variants defines local changes in distant parts of the protein that account for the observed differences of PrPC stability, resistant variants being destabilized compared with sensitive ones. Additive contributions of these sensitivity-modulating mutations to resistance suggest a possible causal relationship between scrapie resistance and lowered stability of the PrP protein.

Selected figure(s)

Figure 1.
Fig. 1. Structure of the OvPrP C-terminal domain. (A) The OvPrP fold and the scrapie-sensitivity-associated mutations. Side chains of scrapie-sensitivity-related residues are represented as green ball-and-stick models in the OvPrP structure. (B Left) Structure of the huPrP crystallographic dimer (27) (one monomer is shown in salmon red, and the other is shown in blue). (B Right) Superimposition of the x-ray structures of OvPrP (this work, red) and of a huPrP domain (blue) constituted by the H3 helix of one monomer and of the rest of the sequence of the other monomer.

Figure 2.
Fig. 2. Structural consequences of scrapie-sensitivity-related mutations. The blue grid corresponds to the 1.0- level contour of the 2Fo - Fc omit map. Maps are calculated by using data in the 15.0- to 2.5-Å-resolution range for the ARQ and VRQ variants and the 15.0- to 2.8-Å-resolution range for the ARR variant. Hydrogen bonds are displayed as dashed lines, and distances of the atoms involved are reported. (Upper) A136V. The Fo[VRQ] - Fo[ARQ] difference map, represented as red and green grids (contour levels: -5.0 and 5.0 , respectively) is superimposed on the ARQ 2Fo - Fc omit map. (Lower) Q171R.

Figures were selected by an automated process.