Identification of Complement Regulatory Domains in Vaccinia Virus Complement Control Protein

Mullick, Jayati; Bernet, John; Panse, Yogesh; Hallihosur, Sharanabasava; Singh, Akhilesh K.; Sahu, Arvind

doi:10.1128/jvi.79.19.12382-12393.2005

Cited by 39 publications

(63 citation statements)

References 60 publications

(80 reference statements)

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“…Armed with this information on DAF, we then analyzed the extent of conservation of residues in DAF and in other C3 convertase regulators determined by mutagenesis to be important, either for cofactor activity or for DAA (12,18,21,22,(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41). Whereas we found an absence of strict conservation of residues which distinguish the two functions, by focusing alignment on the sequence flanking the CCP2 and -3 junction where DAF function resides, we identified differences between those regulators that 1) mediate DAA and 2) mediate cofactor activity.…”

Section: Discussionmentioning

confidence: 99%

Structure-based Mapping of DAF Active Site Residues That Accelerate the Decay of C3 Convertases

Kuttner-Kondo

Hourcade

Anderson

et al. 2007

Journal of Biological Chemistry

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Focused complement activation on foreign targets depends on regulatory proteins that decay the bimolecular C3 convertases. Although this process is central to complement control, how the convertases engage and disassemble is not established. The second and third complement control protein (CCP) modules of the cell surface regulator, decay-accelerating factor (DAF, CD55), comprise the simplest structure mediating this activity. Positioning the functional effects of 31 substitution mutants of DAF CCP2 to -4 on partial structures was previously reported. In light of the high resolution crystal structure of the DAF four-CCP functional region, we now reexamine the effects of these and 40 additional mutations. Moreover, we map six monoclonal antibody epitopes and overlap their effects with those of the amino acid substitutions. The data indicate that the interaction of DAF with the convertases is mediated predominantly by two patches ϳ13 Å apart, one centered around Arg 69 and Arg 96 on CCP2 and the other around Phe 148 and Leu 171 on CCP3. These patches on the same face of the adjacent modules bracket an intermodular linker of critical length (16 Å ). Although the key DAF residues in these patches are present or there are conservative substitutions in all other C3 convertase regulators that mediate decay acceleration and/or provide factor I-cofactor activity, the linker region is highly conserved only in the former. Intra-CCP regions also differ. Linker region comparisons suggest that the active CCPs of the decay accelerators are extended, whereas those of the cofactors are tilted. Intra-CCP comparisons suggest that the two classes of regulators bind different regions on their respective ligands.The C3 convertases of the classical and alternative pathways are the central enzymes of the complement cascade (1). These bimolecular complexes, C4b2a and C3bBb, produce anaphylatoxin C3a, locally amplify C3b deposition, and serve as sites for the assembly of the C5 convertases, C4b2a3b and C3bBb3b. These trimeric convertases, in turn, generate anaphylatoxin C5a and initiate the terminal pathway, leading to formation of lytic C5b-9 membrane attack complexes. The relative rates of assembly and disassembly of the C3 convertases lie at the heart of complement regulation, and their physiologic modulation ensures that complement acts in a proportionate and targeted fashion.To focus complement activation on foreign targets, prevent nearby activation in the fluid phase, and simultaneously protect self tissues from complement-mediated injury, the C3 convertases are controlled by both serum-and cell-associated regulatory proteins (2, 3). Because the convertases assemble on C4b and C3b fragments that condense indiscriminately with free hydroxyl and amino groups on foreign targets and these same acceptor groups are present on all biological membranes, their formation on self cells at the single enzyme level cannot be avoided. To prevent further propagation of the cascade, which would induce self cell injury, self cells possess decay-acc...

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Section: Discussionmentioning

confidence: 99%

Structure-based Mapping of DAF Active Site Residues That Accelerate the Decay of C3 Convertases

Kuttner-Kondo

Hourcade

Anderson

et al. 2007

Journal of Biological Chemistry

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“…2A), and therefore next we sought to determine which of these variant residues in VCP are responsible for its better inhibitory activity toward bovine complement. Being a homolog of the human RCA proteins, VCP possesses the ability to inactivate AP by targeting the AP C3-convertase by supporting the cleavage of C3b by serine protease factor I (termed cofactor activity) and by accelerating the dissociation of C3-convertase (termed decay-accelerating activity) (26,37). We thus generated 11 single amino acid mutants by substituting each of the 11 variant VCP residues onto SPICE template (Fig.…”

Section: Vcp Exhibits Preference In Inhibiting Bovine Alternative Commentioning

confidence: 99%

“…These preformed C3-convertases were then allowed to decay in the presence of SPICE, VCP, or the mutants, and the remaining enzyme activity was quantitated by incubating the enzyme-coated cells with EDTA sera and measuring lysis (34). The ability of SPICE, VCP, and the mutants to act as a cofactor for the factor I-mediated cleavage of human/bovine C3b was measured by performing the fluid phase cofactor assay (26).…”

Section: C3-convertase Decay Acceleration and Factor I Cofactor Assaysmentioning

confidence: 99%

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Species Selectivity in Poxviral Complement Regulators Is Dictated by the Charge Reversal in the Central Complement Control Protein Modules

Yadav

Pyaram

Ahmad

et al. 2012

The Journal of Immunology

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Variola and vaccinia viruses, the two most important members of the family Poxviridae, are known to encode homologs of the human complement regulators named smallpox inhibitor of complement enzymes (SPICE) and vaccinia virus complement control protein (VCP), respectively, to subvert the host complement system. Intriguingly, consistent with the host tropism of these viruses, SPICE has been shown to be more human complement-specific than VCP, and in this study we show that VCP is more bovine complement-specific than SPICE. Based on mutagenesis and mechanistic studies, we suggest that the major determinant for the switch in species selectivity of SPICE and VCP is the presence of oppositely charged residues in the central complement control modules, which help enhance their interaction with factor I and C3b, the proteolytically cleaved form of C3. Thus, our results provide a molecular basis for the species selectivity in poxviral complement regulators.

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“…Vaccinia virus (VACV), the prototypic member of the poxvirus family, encodes a protein called the vaccinia virus complement control protein (VCP), which limits complement activation by inhibiting several early steps of the complement cascade (25,26,36). VCP limits complement activation by dissociating the C3 and C5 convertases, which are necessary to initiate and sustain activation of the cascade, and by acting as a cofactor for the serine protease factor I to promote degradation and inactivation of C3b and C4b (31,36,42,45,46,48). In vitro, VCP has been shown to protect viral particles from complement-mediated neutralization (19,20) and prevent complement-dependent lysis of infected cells (16).…”

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confidence: 99%

The Vaccinia Virus Complement Control Protein Modulates Adaptive Immune Responses during Infection

Girgis

DeHaven

Xiao

et al. 2011

J Virol

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Identification of Complement Regulatory Domains in Vaccinia Virus Complement Control Protein

Abstract: Vaccinia virus encodes a homolog of the human complement regulators named vaccinia virus complement control protein (VCP).

Cited by 39 publications

References 60 publications

Structure-based Mapping of DAF Active Site Residues That Accelerate the Decay of C3 Convertases

Structure-based Mapping of DAF Active Site Residues That Accelerate the Decay of C3 Convertases

Species Selectivity in Poxviral Complement Regulators Is Dictated by the Charge Reversal in the Central Complement Control Protein Modules

The Vaccinia Virus Complement Control Protein Modulates Adaptive Immune Responses during Infection

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