Each of the Three Binding Sites on Complement Factor H Interacts with a Distinct Site on C3b

Jokiranta, T. Sakari; Hellwage, Jens; Koistinen, Vesa; Zipfel, Peter F.; Meri, Seppo

doi:10.1074/jbc.m002903200

Cited by 197 publications

(167 citation statements)

References 53 publications

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“…The N-terminal part of the molecule (CCPs 1-4) is responsible for its complement regulatory activity (Alsenz et al, 1984;Kühn et al, 1995). FH has multiple binding sites for C3b, located within CCPs 1-4, CCPs 12-15 and CCPs 19-20 (Sharma and Pangburn, 1996;Jokiranta et al, 2000), and for heparin, located in CCP7, CCP9, CCPs 12-14, and CCPs 19-20 (Pangburn et al, 1991;Blackmore et al, 1996Blackmore et al, , 1998Ormsby et al, 2006). However, in its native conformation the C-terminal domains contain the preferential interaction site for both C3b/C3d and heparin/ glycosaminoglycans (Oppermann et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

The C-terminus of complement factor H is essential for host cell protection

Józsi

Oppermann

Lambris

et al. 2007

Molecular Immunology

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Complement is a powerful self-amplifying system of innate immune defence with the capacity to eliminate microbes directly. Factor H is a central regulator in plasma which protects host tissue from complement mediated damage. Here we characterize the relevance of surface attached factor H, and study the regulatory activity of factor H on endothelial cells. Although these cells expressed membrane bound regulators, cell bound factor H contributed substantially to complement regulatory activity at the cell surface. Blockade of the C-terminus of factor H with monoclonal antibodies inhibited cell binding of this soluble regulator and resulted in enhanced complement activation on the cells. In the absence of factor H, increased deposition and slower inactivation of C3b resulted in higher amount of membrane attack complexes on the cell surface. When the membrane regulators CD55 and CD59 were removed by enzymatic treatment, complement mediated cell lysis was enhanced in the absence of factor H. Importantly, inhibition of the C-terminus did not compromise the regulatory function of factor H in fluid phase. Altogether these data point to a highly relevant, yet so far underestimated role of factor H for complement control at cellular surfaces, and reveal a decisive role of the factor H C-terminus in host cell recognition and protection.

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Section: Introductionmentioning

confidence: 99%

The C-terminus of complement factor H is essential for host cell protection

Józsi

Oppermann

Lambris

et al. 2007

Molecular Immunology

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“…Factor H is translated from an mRNA of 4.4 kb to a 150 kDa protein that is composed of 20 domains called short consensus repeats (SCR) (Kristensen et al, 1986). In factor H three C3b binding sites and 2 -3 polyanion binding sites are distributed along the approximately 600 Å long molecule (Pangburn et al, 1991;Sharma and Pangburn, 1996;Blackmore et al, 1998;Jokiranta et al, 2000). Factor H inhibits the alternative C pathway by preventing factor B binding to C3b, promoting dissociation of the C3bBb enzyme complex (decay accelerating activity) and by acting as a cofactor for factor I-mediated inactivation of C3b.…”

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confidence: 99%

Secretion of soluble complement inhibitors factor H and factor H-like protein (FHL-1) by ovarian tumour cells

et al. 2002

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We observed that the soluble complement regulators factor H and factor H-like protein were abundantly present in ascites samples as well as in primary tumours of patients with ovarian cancer. RT -PCR and immunoblotting analyses showed that the two complement inhibitors were constitutively produced by the ovarian tumour cell lines SK-OV-3 and Caov-3, but not PA-1 or SW626 cells. The amounts of factor H-like protein secreted were equal to those of factor H. This is exceptional, because e.g. in normal human serum the concentration of factor H-like protein is below 1/10th of that of factor H. In ascites samples the mean level of factor H-like protein (130+55 mg ml 71 ) was 5.5-fold higher than in normal human serum (24+3 mg ml 71 ). Ovarian tumour cells thus preferentially synthesise factor H-like protein, the alternatively spliced short variant of factor H. The tumour cells were found to bind both 125 I-labelled factor H and recombinant factor H-like protein to their surfaces. Surprisingly, the culture supernatants of all of the ovarian tumour cell lines studied, including those of PA-1 and SW626 that did not produce factor H/factor H-like protein, promoted factor I-mediated cleavage of C3b to inactive iC3b. Subsequently, the PA-1 and SW626 cell lines were found to secrete a soluble form of the membrane cofactor protein (CD46). Thus, our studies reveal two novel complement resistance mechanisms of ovarian tumour cells: (i) production of factor H-like protein and factor H and (ii) secretion of soluble membrane cofactor protein. Secretion of soluble complement inhibitors could protect ovarian tumour cells against humoral immune attack and pose an obstacle for therapy with monoclonal antibodies.

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“…The remaining modules are primarily concerned with ensuring factor H discriminates between healthy host tissue (where it acts protectively) and waste or foreign material (where its complement regulatory activities are not manifested). In all, factor H has three distinct binding sites for three discrete regions of C3b (Jokiranta et al, 2000;Sharma and Pangburn, 1996), and three probably separate binding sites for sialic acid/glycosaminoglycans (GAGs) (Meri and Pangburn, 1994;Ormsby et al, 2006) (Fig. 5).…”

Section: Structure-function Relationships In the Regulators Of Complementioning

confidence: 99%

Deciphering complement mechanisms: The contributions of structural biology

Arlaud

Barlow

Gaboriaud

et al. 2007

Molecular Immunology

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Since the resolution of the first three-dimensional structure of a complement component in 1980, considerable efforts have been put into the investigation of this system through structural biology techniques, resulting in about a hundred structures deposited in the Protein Data Bank by the beginning of 2007. By revealing its mechanisms at the atomic level, these approaches significantly improve our understanding of complement, opening the way to the rational design of specific inhibitors. This review is co-authored by some of the researchers currently involved in the structural biology of complement and its purpose is to illustrate, through representative examples, how X-ray crystallography and NMR techniques help us decipher the many sophisticated mechanisms that underlie complement functions.

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Each of the Three Binding Sites on Complement Factor H Interacts with a Distinct Site on C3b

Cited by 197 publications

References 53 publications

The C-terminus of complement factor H is essential for host cell protection

The C-terminus of complement factor H is essential for host cell protection

Secretion of soluble complement inhibitors factor H and factor H-like protein (FHL-1) by ovarian tumour cells

Deciphering complement mechanisms: The contributions of structural biology

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