Allosteric inhibition of complement function by a staphylococcal immune evasion protein

Chen, Hui; Ricklin, Daniel; Hammel, Michal; Garcia, Brandon L.; McWhorter, William J.; Sfyroera, Georgia; Wu, Yanze; Τζέκου, Αποστολία; Li, Sheng; Geisbrecht, Brian V.; Woods, Virgil L.; Lambris, John D.

doi:10.1073/pnas.1003750107

Cited by 81 publications

(111 citation statements)

References 42 publications

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“…The surface of S. suis is armed with molecules that allow it to evade the host's immune defenses through interactions with FH by Fhb (19). Alternatively, some pathogens causing invasive disease inhibit complement activation by targeting C3b, a key molecule in all complement activation pathways, through C3b-binding proteins (18).…”

Section: Discussionmentioning

confidence: 99%

“…Secretion of C3b-binding proteins, such as Ecb and Efb, by S. aureus (17,18) usually results in enhanced complement evasion by consumption of C3b, a key factor in activation of the alternative pathway in blood. It may be that released Fhb in the supernatant is involved in the antiphagocytic ability of S. suis 2 by binding of C3b.…”

Section: Interactions Between Fhb and Fh/c3b/c3dmentioning

confidence: 99%

“…This is demonstrated by the Sbi protein of S. aureus, which forms a ternary complex with FH and C3b, acting as a potent inhibitor of the alternative pathway (16). Also in S. aureus, secretion of C3b-binding proteins (Ecb and Efb) can result in the blocking of C3 convertases of the alternative pathway, which enhances complement evasion (17,18). In our previous study (19), FH binding to the surface of S. suis 2 was reported to involve Fhb, a surface protein with a proline-rich repeat domain and LPXTG motif.…”

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confidence: 99%

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Mechanisms of Host-Pathogen Protein Complex Formation and Bacterial Immune Evasion of Streptococcus suis Protein Fhb

Liu

Gan

Zhang

et al. 2016

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 99%

Section: Interactions Between Fhb and Fh/c3b/c3dmentioning

confidence: 99%

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confidence: 99%

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Mechanisms of Host-Pathogen Protein Complex Formation and Bacterial Immune Evasion of Streptococcus suis Protein Fhb

Liu

Gan

Zhang

et al. 2016

Journal of Biological Chemistry

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“…Protein complexes analyzed by HDX were introduced to an Orbitrap Elite Mass Spectrometer (ThermoFisher Scientific) for electrospray ionization and accurate mass measurements. DXMS Explorer (Sierra Analytics) was used for the calculation of the deuteration level of all of the peptides as described previously (56,57).…”

Section: Methodsmentioning

confidence: 99%

Structural flexibility at a major conserved antibody target on hepatitis C virus E2 antigen

Kong

Lee

Kadam

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Hepatitis C virus (HCV) is a major cause of liver disease, affecting over 2% of the world's population. The HCV envelope glycoproteins E1 and E2 mediate viral entry, with E2 being the main target of neutralizing antibody responses. Structural investigations of E2 have produced templates for vaccine design, including the conserved CD81 receptor-binding site (CD81bs) that is a key target of broadly neutralizing antibodies (bNAbs). Unfortunately, immunization with recombinant E2 and E1E2 rarely elicits sufficient levels of bNAbs for protection. To understand the challenges for eliciting bNAb responses against the CD81bs, we investigated the E2 CD81bs by electron microscopy (EM), hydrogen-deuterium exchange (HDX), molecular dynamics (MD), and calorimetry. By EM, we observed that HCV1, a bNAb recognizing the N-terminal region of the CD81bs, bound a soluble E2 core construct from multiple angles of approach, suggesting components of the CD81bs are flexible. HDX of multiple E2 constructs consistently indicated the entire CD81bs was flexible relative to the rest of the E2 protein, which was further confirmed by MD simulations. However, E2 has a high melting temperature of 84.8°C, which is more akin to proteins from thermophilic organisms. Thus, recombinant E2 is a highly stable protein overall, but with an exceptionally flexible CD81bs. Such flexibility may promote induction of nonneutralizing antibodies over bNAbs to E2 CD81bs, underscoring the necessity of rigidifying this antigenic region as a target for rational vaccine design.hepatitis C virus | E2 | CD81-binding site | conformational flexibility | protein dynamics H epatitis C virus (HCV) is a leading cause of liver cirrhosis and hepatocellular carcinoma, infecting more than 2% of the world's population (1). HCV infection is highly prevalent in developing countries and among marginalized populations, such as injection drug users (IDUs) and prisoners in developed countries (2). Effective direct-acting antiviral (DAA) drugs have been developed recently to curb the advance of HCV (3, 4). Nevertheless, new infections are on the rise among young IDUs in developed countries and along drug-trafficking routes (2, 5, 6). Because DAA treatment is prohibitively expensive and does not prevent reinfection (7,8), an effective vaccine is essential for management of the global HCV epidemic (9-11).Despite the significant public health burden, no effective prophylactic vaccine against HCV has been developed. High genetic variability of the virus is a major barrier, particularly in the E1 and E2 envelope glycoproteins that are the primary neutralizing antibody (NAb) targets. E2, the receptor-binding protein, mediates cell entry by interacting with the tetraspanin CD81 and several other cell surface molecules (12, 13). The crystal structure of the E2 core domain (E2c) consists of a central β-sandwich flanked by "front" and "back" layers (14) (Fig. 1). The CD81-binding site (CD81bs) has been mapped by mutagenesis and electron microscopy (EM) to various elements: a conserved N-terminal...

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“…Both Ecb and Efb contribute to the pathogenesis of staphylococcal infections (33,34) by interfering with two host defense mechanisms. First, they inhibit complement activation by preventing formation of the C3b-containing convertases (35,36). Second, they inhibit the adaptive immune responses by blocking binding of C3dg, a physiological cleavage fragment of C3b, to complement receptor 2 (CR2, CD21) on B cells (37).…”

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confidence: 99%

Staphylococcal Ecb Protein and Host Complement Regulator Factor H Enhance Functions of Each Other in Bacterial Immune Evasion

Amdahl

Jongerius

Meri

et al. 2013

The Journal of Immunology

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Staphylococcus aureus is a major human pathogen causing more than a tenth of all septicemia cases and often superficial and deep infections in various tissues. One of the immune evasion strategies of S. aureus is to secrete proteins that bind to the central complement opsonin C3b. One of these, extracellular complement binding protein (Ecb), is known to interfere directly with functions of C3b. Because C3b is also the target of the physiological plasma complement regulator, factor H (FH), we studied the effect of Ecb on the complement regulatory functions of FH. We show that Ecb enhances acquisition of FH from serum onto staphylococcal surfaces. Ecb and FH enhance mutual binding to C3b and also the function of each other in downregulating complement activation. Both Ecb and the C-terminal domains 19–20 of FH bind to the C3d part of C3b. We show that the mutual enhancing effect of Ecb and FH on binding to C3b depends on binding of the FH domain 19 to the C3d part of C3b next to the binding site of Ecb on C3d. Our results show that Ecb, FH, and C3b form a tripartite complex. Upon exposure of serum-sensitive Haemophilus influenzae to human serum, Ecb protected the bacteria, and this effect was enhanced by the addition of the C-terminal domains 19–20 of FH. This finding indicates that the tripartite complex formation could give additional protection to bacteria and that S. aureus is thereby able to use host FH and bacterial Ecb in a concerted action to eliminate C3b at the site of infection.

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Allosteric inhibition of complement function by a staphylococcal immune evasion protein

Cited by 81 publications

References 42 publications

Mechanisms of Host-Pathogen Protein Complex Formation and Bacterial Immune Evasion of Streptococcus suis Protein Fhb

Mechanisms of Host-Pathogen Protein Complex Formation and Bacterial Immune Evasion of Streptococcus suis Protein Fhb

Structural flexibility at a major conserved antibody target on hepatitis C virus E2 antigen

Staphylococcal Ecb Protein and Host Complement Regulator Factor H Enhance Functions of Each Other in Bacterial Immune Evasion

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