4j8r

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Structure of an octapeptide repeat of the prion protein bound to the POM2 Fab antibody fragment

Structural highlights

4j8r is a 6 chain structure with sequence from Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.303Å
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

PRIO_MOUSE Note=Found in high quantity in the brain of humans and animals infected with degenerative neurological diseases such as kuru, Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler syndrome (GSS), scrapie, bovine spongiform encephalopathy (BSE), transmissible mink encephalopathy (TME), etc.

Function

PRIO_MOUSE May play a role in neuronal development and synaptic plasticity. May be required for neuronal myelin sheath maintenance. May play a role in iron uptake and iron homeostasis. Soluble oligomers are toxic to cultured neuroblastoma cells and induce apoptosis (in vitro) (By similarity). Association with GPC1 (via its heparan sulfate chains) targets PRNP to lipid rafts. Also provides Cu(2+) or ZN(2+) for the ascorbate-mediated GPC1 deaminase degradation of its heparan sulfate side chains.[1] [2] [3] [4]

Publication Abstract from PubMed

Prion diseases are progressive, infectious neurodegenerative disorders caused primarily by the misfolding of the cellular prion protein (PrPc ) into an insoluble, protease-resistant, aggregated isoform termed PrPsc . In native conditions, PrPc has a structured C-terminal domain and a highly flexible N-terminal domain. A part of this N-terminal domain consists of 4-5 repeats of an unusual glycine-rich, eight amino acids long peptide known as the octapeptide repeat (OR) domain. In this article, we successfully report the first crystal structure of an OR of PrPc bound to the Fab fragment of the POM2 antibody. The structure was solved at a resolution of 2.3 A by molecular replacement. Although several studies have previously predicted a beta-turn-like structure of the unbound ORs, our structure shows an extended conformation of the OR when bound to a molecule of the POM2 Fab indicating that the bound Fab disrupts any putative native beta turn conformation of the ORs. Encouraging results from several recent studies have shown that administering small molecule ligands or antibodies targeting the OR domain of PrP result in arresting the progress of peripheral prion infections both in ex vivo and in in vivo models. This makes the structural study of the interactions of POM2 Fab with the OR domain very important as it would help us to design smaller and tighter binding OR ligands.

The crystal structure of an octapeptide repeat of the Prion protein in complex with a Fab fragment of the POM2 antibody.,Swayampakula M, Baral PK, Aguzzi A, Kav NN, James MN Protein Sci. 2013 Apr 30. doi: 10.1002/pro.2270. PMID:23629842[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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See Also

References

  1. ↑ Mani K, Cheng F, Havsmark B, Jonsson M, Belting M, Fransson LA. Prion, amyloid beta-derived Cu(II) ions, or free Zn(II) ions support S-nitroso-dependent autocleavage of glypican-1 heparan sulfate. J Biol Chem. 2003 Oct 3;278(40):38956-65. Epub 2003 May 5. PMID:12732622 doi:10.1074/jbc.M300394200
  2. ↑ Steele AD, Emsley JG, Ozdinler PH, Lindquist S, Macklis JD. Prion protein (PrPc) positively regulates neural precursor proliferation during developmental and adult mammalian neurogenesis. Proc Natl Acad Sci U S A. 2006 Feb 28;103(9):3416-21. Epub 2006 Feb 21. PMID:16492732 doi:10.1073/pnas.0511290103
  3. ↑ Lauren J, Gimbel DA, Nygaard HB, Gilbert JW, Strittmatter SM. Cellular prion protein mediates impairment of synaptic plasticity by amyloid-beta oligomers. Nature. 2009 Feb 26;457(7233):1128-32. doi: 10.1038/nature07761. PMID:19242475 doi:10.1038/nature07761
  4. ↑ Singh A, Kong Q, Luo X, Petersen RB, Meyerson H, Singh N. Prion protein (PrP) knock-out mice show altered iron metabolism: a functional role for PrP in iron uptake and transport. PLoS One. 2009 Jul 1;4(7):e6115. doi: 10.1371/journal.pone.0006115. PMID:19568430 doi:10.1371/journal.pone.0006115
  5. ↑ Swayampakula M, Baral PK, Aguzzi A, Kav NN, James MN. The crystal structure of an octapeptide repeat of the Prion protein in complex with a Fab fragment of the POM2 antibody. Protein Sci. 2013 Apr 30. doi: 10.1002/pro.2270. PMID:23629842 doi:10.1002/pro.2270

Contents


PDB ID 4j8r

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OCA

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