Evidence That C1q Binds Specifically to CH2-like Immunoglobulin Motifs Present in the Autoantigen Calreticulin and Inter
详细信息 查看全文
- 作者：Helena Kovacs ; Iain D. Campbell ; Peter Strong ; Steven Johnson ; Frank J. Ward ; Kenneth B. M. Reid ; and Paul Eggleton
- 刊名：Biochemistry
- 出版年：1998
- 出版时间：December 22, 1998
- 年：1998
- 卷：37
- 期：51
- 页码：17865 - 17874
- 全文大小：128K
- 年卷期：v.37,no.51(December 22, 1998)
- ISSN：1520-4995
文摘
Calreticulin (CRT) is located predominantly in the endoplasmic reticulum (ER) of cells, whereit functions as a quality control controller of protein folding. However, CRT is also a prevalent autoantigenin patients with systemic lupus erythematosus (SLE), where its release from the cell may arise as a resultsof dysfunctional apoptosis and inefficient removal of ER vesicles, which are an abundant source of CRTand other autoantigens. Indicative of this is the presence of autoantibodies against CRT in the sera of40-60% of all SLE patients. Once released into the circulation, CRT might bind directly to C1q and wehave suggested that this association may result in a defect in C1q-mediated clearance of antigen-antibodycomplexes. It has been previously shown that CRT under physiological salt conditions binds to the globularhead of C1q. It is known that the globular head region of C1q binds to the CH2 domain in the Fc portionof immunoglobulin 
hars/gamma.gif" BORDER=0 > (IgG). The N-terminal half of CRT contains a number of short regions of 7-10amino acids that show sequence similarity to the putative C1q binding region in the CH2 domain of IgG.By use of a series of 92 overlapping CRT synthetic peptides, a number of C1q binding sites on the CRTmolecule have been identified, including several containing a CH2 -like motif similar to the ExKxKx C1qbinding motif found in the CH2 domain of IgG. A number of these peptides were shown to inhibit bindingof C1q to IgG and reduce binding of native CRT to C1q. Moreover, several of the peptides were capableof inhibiting the classical pathway of complement activation. These studies have identified specific bindingsites on the CRT molecule for C1q and lend support to the hypothesis that interaction of CRT with C1qmay interfere with the ability of C1q to associate with immune complexes in autoimmune-related disorders.
hars/gamma.gif" BORDER=0 > (IgG). The N-terminal half of CRT contains a number of short regions of 7-10amino acids that show sequence similarity to the putative C1q binding region in the CH2 domain of IgG.By use of a series of 92 overlapping CRT synthetic peptides, a number of C1q binding sites on the CRTmolecule have been identified, including several containing a CH2 -like motif similar to the ExKxKx C1qbinding motif found in the CH2 domain of IgG. A number of these peptides were shown to inhibit bindingof C1q to IgG and reduce binding of native CRT to C1q. Moreover, several of the peptides were capableof inhibiting the classical pathway of complement activation. These studies have identified specific bindingsites on the CRT molecule for C1q and lend support to the hypothesis that interaction of CRT with C1qmay interfere with the ability of C1q to associate with immune complexes in autoimmune-related disorders.