Complement protein C1q recognizes a conformationally modified form of the prion protein

被引:43
作者
Blanquet-Grossard, F
Thielens, NM
Vendrely, C
Jamin, M
Arlaud, GJ
机构
[1] Inst Biol Struct Jean Pierre Ebel, Lab Enzymol Mol, F-38027 Grenoble, France
[2] Dept Reponse & Dynam Cellulaires, Lab Biophys Mol & Cellulaire, F-38054 Grenoble, France
关键词
D O I
10.1021/bi047370a
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Several studies have suggested the implication of the classical complement pathway in the early stages of prion disease pathogenesis. To explore this hypothesis, surface plasmon resonance spectroscopy was used to test the ability of human C1q to recognize mouse PrP immobilized on a sensor chip. In this configuration, C1q bound avidly to PrP, with a K-D of 5.4 nM (k(on) = 2.4 x 10(5) M-1 s(-1); k(off) = 1.3 x 10(-3) s(-1)). The isolated C1q globular domain also bound to immobilized PrP, although with a higher K-D (238 nM), due to a decreased k(on) (4.2 x 10(3) M-1 s(-1)). Interaction was strongly enhanced by Cu2+ ions, with a 10-fold increase in overall binding in the presence of 10 mu M CuSO4, without significant modification of the kinetic parameters. In contrast, using the same technique, no interaction was detected between immobilized C1q and soluble PrP. Likewise, gel filtration and chemical cross-linking analyses yielded no evidence for an interaction between these proteins in solution. Comparative analysis of the antigenic reactivity of soluble and immobilized PrP was performed by ELISA and surface plasmon resonance spectroscopy, respectively, using anti-PrP monoclonal antibodies. This analysis provides evidence that immobilized PrP undergoes a major conformational change in the sequence stretch 141GND-WEDRYYRENMYRYPNQ159 located in its C-terminal globular domain. It is concluded that immobilized PrP undergoes structural modifications that possibly mimic the conformational changes occurring during conversion to the pathological isoform. and that C1q represents a natural sensor of these changes. Pathological implications of this recognition property are discussed in light of recent reports.
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页码:4349 / 4356
页数:8
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