4hmr

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Crystal structure of mutant rabbit PRP 121-230 (S170N/S174N)

Structural highlights

4hmr is a 2 chain structure with sequence from Oryctolagus cuniculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

PRIO_RABIT 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_RABIT 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). 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 (By similarity).

Publication Abstract from PubMed

Susceptibility of a particular species to prion disease is affected by small differences in the sequence of PrP and correlates with the propensity of its PrP to assume the beta-state. A helix-cap motif in the beta2-alpha2-loop of native alpha-helical rabbit PrP, a resistant species, contains sequence differences that influence intra- and interspecies transmission. To determine the effect the helix-cap motif on beta-state refolding propensity, we mutated S170N, S174N, and S170N/S174N of the rabbit PrP helix-cap to resemble that of hamster PrP and conversely, N170S, N174S, and N170S/N174S of hamster PrP to resemble the helix-cap of rabbit PrP. High-resolution crystal structures (1.45-1.6 A) revealed that these mutations ablate hydrogen-bonding interactions within the helix-cap motif in rabbit PrP(C). They also alter the beta-state-misfolding propensity of PrP; the serine mutations in hamster PrP decrease the propensity up to 35%, whereas the asparagine mutations in rabbit PrP increase it up to 42%. Rapid dilution of rabbit and hamster into beta-state buffer conditions causes quick conversion to beta-state monomers. Kinetic monitoring using size-exclusion chromatography showed that the monomer population decreases exponentially mirrored by an increase in an octameric species. The monomer-octamer transition rates are faster for hamster than for rabbit PrP. The N170S/N174S mutant of hamster PrP has a smaller octamer component at the endpoint compared to the wild-type, whereas the kinetics of octamer formation in mutant and wild-type rabbit PrP are comparable. These findings demonstrate that the sequence of the beta2-alpha2 helix-cap affects refolding to the beta-state and subsequently, may influence susceptibility to prion disease.

N-Terminal Helix-Cap in alpha-Helix 2 Modulates beta-State Misfolding in Rabbit and Hamster Prion Proteins.,Sweeting B, Brown E, Khan MQ, Chakrabartty A, Pai EF PLoS One. 2013 May 10;8(5):e63047. doi: 10.1371/journal.pone.0063047. Print 2013. PMID:23675452^[1]

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

References

↑ Sweeting B, Brown E, Khan MQ, Chakrabartty A, Pai EF. N-Terminal Helix-Cap in alpha-Helix 2 Modulates beta-State Misfolding in Rabbit and Hamster Prion Proteins. PLoS One. 2013 May 10;8(5):e63047. doi: 10.1371/journal.pone.0063047. Print 2013. PMID:23675452 doi:10.1371/journal.pone.0063047