Mapping of the domains required for decay acceleration activity of the human factor H‐like protein 1 and factor H

Kühn, Sabine; Zipfel, Peter F.

doi:10.1002/eji.1830261017

Cited by 154 publications

(106 citation statements)

References 21 publications

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“…Despite the fact that FHL-1 bound more efficiently to BbCRASP-1, factor H exerted up to 6-fold stronger cofactor activity. This observation is explained by the higher decay-accelerating activity of factor H (53).…”

Section: Discussionmentioning

confidence: 91%

Complement Resistance of Borrelia burgdorferi Correlates with the Expression of BbCRASP-1, a Novel Linear Plasmid-encoded Surface Protein That Interacts with Human Factor H and FHL-1 and Is Unrelated to Erp Proteins

Kraiczy

Hellwage

Skerka

et al. 2004

Journal of Biological Chemistry

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216

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The etiologic agent of Lyme disease, Borrelia burgdorferi, is capable of circumventing the immune defense of a variety of potential vertebrate hosts. Previous work has shown that interaction of host-derived complement regulators, factor H and factor H-like protein 1 (FHL-1), with up to five complement regulator-acquiring surface proteins (CRASPs) expressed by resistant B. burgdorferi sensu lato isolates conferred complement resistance. In addition expression of CRASP-1 is directly correlated with complement resistance of Borrelia species. This work describes the functional characterization of BbCRASP-1 as the dominant factor H and FHL-1-binding protein of B. burgdorferi. The corresponding gene, zs7.a68, is located on the linear plasmid lp54 and is different from factor H-binding Erp proteins that are encoded by genes localized on circular plasmids (cp32). Deletion mutants of BbCRASP-1 were generated, and a high affinity binding site for factor H and FHL-1 was mapped to the C terminus of BbCRASP-1. Similarly, the predominant binding site of factor H and FHL-1 was localized to the short consensus repeat 7. Factor H and FHL-1 maintain their cofactor activity for factor I-mediated C3b inactivation when bound to BbCRASP-1, and factor H is up to 6-fold more efficient in mediating C3b conversion than FHL-1. In conclusion, BbCRASP-1 (i) binds the host complement regulators factor H and FHL-1 with high affinity, (ii) is the key molecule of the complement resistance of spirochetes, and (iii) is distinct from the Erp protein family. Thus, BbCRASP-1 most likely contributes to persistence of B. burgdorferi and to pathogenesis of Lyme disease.

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Section: Discussionmentioning

confidence: 91%

Complement Resistance of Borrelia burgdorferi Correlates with the Expression of BbCRASP-1, a Novel Linear Plasmid-encoded Surface Protein That Interacts with Human Factor H and FHL-1 and Is Unrelated to Erp Proteins

Kraiczy

Hellwage

Skerka

et al. 2004

Journal of Biological Chemistry

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216

217

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“…Mouse mAb anti‐human HA (clone 12CA5; without preservatives or stabilizers) was purchased from Roche. Expression of recombinant peptides CCP1‐4, CCP1‐5, CCP1‐6, CCP6‐8, CCP15‐19, CCP8‐20 and CCP18‐20 in Pichia pastoris was described elsewhere (Kühn et al , 1995; Kühn and Zipfel, 1996). Generation of the polyclonal rabbit anti‐CFHR‐1 antisera was described elsewhere (Heinen et al , 2009).…”

Section: Methodsmentioning

confidence: 99%

ThePlasmodium falciparumblood stages acquire factor H family proteins to evade destruction by human complement

Rosa

Flammersfeld

Ngwa

et al. 2015

Cellular Microbiology

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SummaryThe acquisition of regulatory proteins is a means of blood‐borne pathogens to avoid destruction by the human complement. We recently showed that the gametes of the human malaria parasite Plasmodium falciparum bind factor H (FH) from the blood meal of the mosquito vector to assure successful sexual reproduction, which takes places in the mosquito midgut. While these findings provided a first glimpse of a complex mechanism used by Plasmodium to control the host immune attack, it is hitherto not known, how the pathogenic blood stages of the malaria parasite evade destruction by the human complement. We now show that the human complement system represents a severe threat for the replicating blood stages, particularly for the reinvading merozoites, with complement factor C3b accumulating on the surfaces of the intraerythrocytic schizonts as well as of free merozoites. C3b accumulation initiates terminal complement complex formation, in consequence resulting in blood stage lysis. To inactivate C3b, the parasites bind FH as well as related proteins FHL‐1 and CFHR‐1 to their surface, and FH binding is trypsin‐resistant. Schizonts acquire FH via two contact sites, which involve CCP modules 5 and 20. Blockage of FH‐mediated protection via anti‐FH antibodies results in significantly impaired blood stage replication, pointing to the plasmodial complement evasion machinery as a promising malaria vaccine target.

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“…This indicates that the binding site for the fH SCRs 1-5 was lost on the C3b 53). Later, the amino-terminal binding site was studied using recombinant fH fragments in an ELISA assay, and SCR1-4 was the shortest fragment that was found to display decay-accelerating activity (37). By means of a combination of several monoclonal anti-fH Abs mapped to the recombinant fH fragments, an additional C3b binding site was mapped on fH (38).…”

Section: Binding Of the Fh Constructs To The C3b Fragments C3c And C3dmentioning

confidence: 99%

“…It has been suggested that a total of three C3b-binding sites exist on fH. One has been located to the amino-terminal tryptic fragment (SCR1-6a) (33,34) and further mapped by functional assays to SCRs 1-4 (35)(36)(37). The other two binding sites have not yet been well characterized.…”

Section: Introductionmentioning

confidence: 99%

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

Jokiranta¹,

Hellwage²,

Koistinen³

et al. 2000

Journal of Biological Chemistry

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197

157

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Mapping of the domains required for decay acceleration activity of the human factor H‐like protein 1 and factor H

Cited by 154 publications

References 21 publications

Complement Resistance of Borrelia burgdorferi Correlates with the Expression of BbCRASP-1, a Novel Linear Plasmid-encoded Surface Protein That Interacts with Human Factor H and FHL-1 and Is Unrelated to Erp Proteins

Complement Resistance of Borrelia burgdorferi Correlates with the Expression of BbCRASP-1, a Novel Linear Plasmid-encoded Surface Protein That Interacts with Human Factor H and FHL-1 and Is Unrelated to Erp Proteins

ThePlasmodium falciparumblood stages acquire factor H family proteins to evade destruction by human complement

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

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