Abstract
| Original language | English |
|---|---|
| Article number | 29 |
| Number of pages | 16 |
| Journal | BMC Biochemistry |
| Volume | 10 |
| DOIs | |
| Publication status | Published - 2009 |
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Keywords
- creutzfeldt-jakob-disease
- in-vitro conversion
- susceptibility-linked polymorphisms
- bovine spongiform encephalopathy
- cyclic amplification
- scrapie susceptibility
- natural scrapie
- monoclonal-antibodies
- insert mutation
- resistant forms
Cite this
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Prion protein self-peptides modulate prion interactions and conversion. / Rigter, A.; Priem, J.; Timmers-Parohi, D.; Langeveld, J.P.M.; van Zijderveld, F.G.; Bossers, A.
In: BMC Biochemistry, Vol. 10, 29, 2009.Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - Prion protein self-peptides modulate prion interactions and conversion
AU - Rigter, A.
AU - Priem, J.
AU - Timmers-Parohi, D.
AU - Langeveld, J.P.M.
AU - van Zijderveld, F.G.
AU - Bossers, A.
N1 - 29
PY - 2009
Y1 - 2009
N2 - Background: Molecular mechanisms underlying prion agent replication, converting host-encoded cellular prion protein (PrPC) into the scrapie associated isoform (PrPSc), are poorly understood. Selective self-interaction between PrP molecules forms a basis underlying the observed differences of the PrPC into PrPSc conversion process (agent replication). The importance of previously peptide-scanning mapped ovine PrP self-interaction domains on this conversion was investigated by studying the ability of six of these ovine PrP based peptides to modulate two processes; PrP self-interaction and conversion. Results: Three peptides (octarepeat, binding domain 2- and C-terminal) were capable of inhibiting self-interaction of PrP in a solid-phase PrP peptide array. Three peptides (N-terminal, binding domain 2, and amyloidogenic motif) modulated prion conversion when added before or after initiation of the prion protein misfolding cyclic amplification (PMCA) reaction using brain homogenates. The C-terminal peptides (core region and C-terminal) only affected conversion (increased PrPres formation) when added before mixing PrPC and PrPSc, whereas the octarepeat peptide only affected conversion when added after this mixing. Conclusion: This study identified the putative PrP core binding domain that facilitates the PrPC-PrPSc interaction (not conversion), corroborating evidence that the region of PrP containing this domain is important in the species-barrier and/or scrapie susceptibility. The octarepeats can be involved in PrPC-PrPSc stabilization, whereas the N-terminal glycosaminoglycan binding motif and the amyloidogenic motif indirectly affected conversion. Binding domain 2 and the C-terminal domain are directly implicated in PrPC self-interaction during the conversion process and may prove to be prime targets in new therapeutic strategy development, potentially retaining PrPC function. These results emphasize the importance of probable PrPC-PrPC and required PrPC-PrPSc interactions during PrP conversion. All interactions are probably part of the complex process in which polymorphisms and species barriers affect TSE transmission and susceptibility
AB - Background: Molecular mechanisms underlying prion agent replication, converting host-encoded cellular prion protein (PrPC) into the scrapie associated isoform (PrPSc), are poorly understood. Selective self-interaction between PrP molecules forms a basis underlying the observed differences of the PrPC into PrPSc conversion process (agent replication). The importance of previously peptide-scanning mapped ovine PrP self-interaction domains on this conversion was investigated by studying the ability of six of these ovine PrP based peptides to modulate two processes; PrP self-interaction and conversion. Results: Three peptides (octarepeat, binding domain 2- and C-terminal) were capable of inhibiting self-interaction of PrP in a solid-phase PrP peptide array. Three peptides (N-terminal, binding domain 2, and amyloidogenic motif) modulated prion conversion when added before or after initiation of the prion protein misfolding cyclic amplification (PMCA) reaction using brain homogenates. The C-terminal peptides (core region and C-terminal) only affected conversion (increased PrPres formation) when added before mixing PrPC and PrPSc, whereas the octarepeat peptide only affected conversion when added after this mixing. Conclusion: This study identified the putative PrP core binding domain that facilitates the PrPC-PrPSc interaction (not conversion), corroborating evidence that the region of PrP containing this domain is important in the species-barrier and/or scrapie susceptibility. The octarepeats can be involved in PrPC-PrPSc stabilization, whereas the N-terminal glycosaminoglycan binding motif and the amyloidogenic motif indirectly affected conversion. Binding domain 2 and the C-terminal domain are directly implicated in PrPC self-interaction during the conversion process and may prove to be prime targets in new therapeutic strategy development, potentially retaining PrPC function. These results emphasize the importance of probable PrPC-PrPC and required PrPC-PrPSc interactions during PrP conversion. All interactions are probably part of the complex process in which polymorphisms and species barriers affect TSE transmission and susceptibility
KW - creutzfeldt-jakob-disease
KW - in-vitro conversion
KW - susceptibility-linked polymorphisms
KW - bovine spongiform encephalopathy
KW - cyclic amplification
KW - scrapie susceptibility
KW - natural scrapie
KW - monoclonal-antibodies
KW - insert mutation
KW - resistant forms
U2 - 10.1186/1471-2091-10-29
DO - 10.1186/1471-2091-10-29
M3 - Article
VL - 10
JO - BMC Biochemistry
JF - BMC Biochemistry
SN - 1471-2091
M1 - 29
ER -