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Motif-grafted antibodies containing the replicative interface of cellular PrP are specific for PrPSc

Moroncini, G; Kanu, N; Solforosi, L; Abalos, G; Telling, GC; Head, M; Ironside, J; ... Williamson, RA; + view all (2004) Motif-grafted antibodies containing the replicative interface of cellular PrP are specific for PrPSc. P NATL ACAD SCI USA , 101 (28) 10404 - 10409. 10.1073/pnas.0403522101.

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Abstract

Prion diseases are closely associated with the conversion of the cellular prion protein (PrPc) to an abnormal conformer (PrPsc) [Prusiner, S. B. (1998) Proc. Nad. Acad. Sci. USA 95, 13363-13383]. Monoclonal antibodies that bind epitopes comprising residues 96-104 and 133-158 of PrPc potently inhibit this process, presumably by preventing heterodimeric association of PrPc and PrPsc, and suggest that these regions of PrPc may be critical components of the PrPC-PrPSc replicative interface. We reasoned that transplanting PrP sequence corresponding to these regions into a suitable carrier molecule, such as an antibody, could impart specific recognition of disease-associated forms of PrP. To test this hypothesis, polypeptides containing PrP sequence between residues 89-112 or 136-158 were used to replace the extended heavy chain complementarity-determining region 3 of an IgG antibody specific for the envelope glycoprotein of HIV-1. Herein the resulting engineered PrP-IgGs are shown to bind specifically to infective fractions of PrP in mouse, human, and hamster prion-infected tissues, but not to PrPc, other cellular components, or the HIV-1 envelope. PrPsc reactivity was abolished when the sequence of the PrP 89-112 and 136-158 grafts was mutated, scrambled, or N-terminally truncated. Our findings suggest that residues within the 89-112 and 136-158 segments of PrPc are key components of one face of the PrPC-PrPSc complex. PrPSc-specific antibodies produced by the approach described may find widespread application in the study of prion biology and replication and in the detection of infectious prions in human and animal materials.

Type: Article
Title: Motif-grafted antibodies containing the replicative interface of cellular PrP are specific for PrPSc
DOI: 10.1073/pnas.0403522101
Keywords: PRION PROTEIN, NEUROBLASTOMA-CELLS, MONOCLONAL-ANTIBODY, BINDING, INHIBITION, EPITOPE, PROPAGATION, SEQUENCE, HIV-1, BSE
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Structural and Molecular Biology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology
URI: http://discovery.ucl.ac.uk/id/eprint/179942
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