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The oligomerization properties of prion protein are restricted to the H2H3 domain
Author(s) -
Chakroun Nesrine,
Prigent Stéphanie,
Dreiss Cécile A.,
Noinville Sylvie,
Chapuis Céline,
Fraternali Franca,
Rezaei Human
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.09-153924
Subject(s) - chemistry , kinetics , biophysics , depolymerization , mutagenesis , molecular dynamics , prion protein , mutant , polymerization , point mutation , biochemistry , biology , polymer , gene , computational chemistry , medicine , physics , disease , organic chemistry , pathology , quantum mechanics
The propensity of the prion protein (PrP) to adopt different structures is a clue to its pathological behavior. The determination of the region involved in the PrP C to PrP Sc conversion is fundamental for the understanding of the mechanisms underlying this process at the molecular level. In this paper, the polymerization of the helical H2H3 domain of ovine PrP (OvPrP) was compared to the full‐length construct (using chromatography and light scattering). We show that the oligomerization patterns are identical, although the H2H3 domain has a higher polymerization rate. Furthermore, the depolymerization kinetics of purified H2H3 oligomers compared to those purified from the full‐length PrP reveal that regions outside H2H3 do not significantly contribute to the oligomerization process. By combining rational mutagenesis and molecular dynamics to investigate the early stages of H2H3 oligomerization, we observe a conformationally stable β‐sheet structure that we propose as a possible nucleus for oligomerization; we also show that single point mutations in H2 and H3 present structural polymorphisms and oligomerization properties that could constitute the basis of species or strain variability.—Chakroun, N., Prigent, S., Dreiss, C. A., Noinville, S., Chapuis, C., Fraternali, F., Rezaei, H. The oligomerization properties of prion protein are restricted to the H2H3 domain. FASEB J . 24, 3222–3231 (2010). www.fasebj.org