Identification of Functional Domains in Kaposica, the Complement Control Protein Homolog of Kaposi's Sarcoma-Associated Herpesvirus (Human Herpesvirus 8)

Mullick, Jayati; Singh, Akhilesh K.; Panse, Yogesh; Yadav, Vivekanand; Bernet, John; Sahu, Arvind

doi:10.1128/jvi.79.9.5850-5856.2005

Cited by 31 publications

(38 citation statements)

References 33 publications

(37 reference statements)

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“…The point mutants Arg20Gln/Arg33Gln/Arg35Gln and Lys64Gln/Lys65Gln/Lys88Gln did not bind to heparin, which localizes the heparin binding site to CCP1, stretching in to CCP2. Heparin binding to CCP1 was also observed in (Mullick et al, 2005). Single point mutations were not as defective in heparin binding as the corresponding triple mutant, indicating that the interaction is dependent on several bonds between the heparin molecule and different amino acids in KCP, which agrees well with what has been observed for most other heparin-protein interactions (Capila and Linhardt, 2002).…”

Section: Discussionsupporting

confidence: 84%

The Kaposi's sarcoma-associated herpesvirus complement control protein (KCP) binds to heparin and cell surfaces via positively charged amino acids in CCP1–2

Mark

Lee

Spiller

et al. 2006

Molecular Immunology

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Section: Discussionsupporting

confidence: 84%

The Kaposi's sarcoma-associated herpesvirus complement control protein (KCP) binds to heparin and cell surfaces via positively charged amino acids in CCP1–2

Mark

Lee

Spiller

et al. 2006

Molecular Immunology

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“…Alternatively, the dissociation of C2a by the domain 1 could be a result of a conformational change in the vWFA domain. Previous observations on domain mapping of other viral complement regulators have shown that domains 1-2 are the minimum domains important for CP DAA in Kaposica (48) and soluble complement control protein homolog of herpesvirus saimiri (49). It is therefore possible that like VCP, domain 1 in these proteins too contributes to dissociation of C2a from the CP C3 convertase and other domains play a supportive role in binding to C4b.…”

Section: Vcp Domains Critical For Daasmentioning

confidence: 99%

“…A similar mechanism could also be operative for the interaction of VCP with C4b and factor I. Because domain requirements for ligand binding and CFAs in viral (34,48,49,54) and human complement regulators (55)(56)(57)(58)(59)(60)(61)(62) are conserved, it could be inferred that the recognition sites for C3b/C4b and factor I are spatially conserved in both human and viral complement regulators, and that they employ a common mechanism to inactivate C3b and C4b.…”

Section: Vcp Domains Critical For Factor I Cfasmentioning

confidence: 99%

Domain Swapping Reveals Complement Control Protein Modules Critical for Imparting Cofactor and Decay-Accelerating Activities in Vaccinia Virus Complement Control Protein

Ahmad

Raut

Pyaram

et al. 2010

The Journal of Immunology

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Vaccinia virus encodes a structural and functional homolog of human complement regulators named vaccinia virus complement control protein (VCP). This four-complement control protein domain containing secretory protein is known to inhibit complement activation by supporting the factor I-mediated inactivation of complement proteins, proteolytically cleaved form of C3 (C3b) and proteolytically cleaved form of C4 (C4b) (termed cofactor activity), and by accelerating the irreversible decay of the classical and to a limited extent of the alternative pathway C3 convertases (termed decay-accelerating activity [DAA]). In this study, we have mapped the VCP domains important for its cofactor activity and DAA by swapping its individual domains with those of human decay-accelerating factor (CD55) and membrane cofactor protein (MCP; CD46). Our data indicate the following: 1) swapping of VCP domain 2 or 3, but not 1, with homologous domains of decay-accelerating factor results in loss in its C3b and C4b cofactor activities; 2) swapping of VCP domain 1, but not 2, 3, or 4 with corresponding domains of MCP results in abrogation in its classical pathway DAA; and 3) swapping of VCP domain 1, 2, or 3, but not 4, with homologous MCP domains have marked effect on its alternative pathway DAA. These functional data together with binding studies with C3b and C4b suggest that in VCP, domains 2 and 3 provide binding surface for factor I interaction, whereas domain 1 mediates dissociation of C2a and Bb from the classical and alternative pathway C3 convertases, respectively.

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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%

“…As shown in Table 4, this analysis yielded DAF homologs from a variety of species as well as ϳ10 other proteins. Among known proteins having DAA are CR1 (site 1; CCP1 to -3) (21), Kaposica (22), mouse Crry (23), and the recently reported but only partially character- important residues labeled (12, 18, 21, 22, 25-41). DAF-2, CCP2 of DAF; CR1-1, CCP1 of CR1, etc.…”

Section: Correlation Of the Daf Active Site Residues With Correspondimentioning

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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Identification of Functional Domains in Kaposica, the Complement Control Protein Homolog of Kaposi's Sarcoma-Associated Herpesvirus (Human Herpesvirus 8)

Cited by 31 publications

References 33 publications

The Kaposi's sarcoma-associated herpesvirus complement control protein (KCP) binds to heparin and cell surfaces via positively charged amino acids in CCP1–2

The Kaposi's sarcoma-associated herpesvirus complement control protein (KCP) binds to heparin and cell surfaces via positively charged amino acids in CCP1–2

Domain Swapping Reveals Complement Control Protein Modules Critical for Imparting Cofactor and Decay-Accelerating Activities in Vaccinia Virus Complement Control Protein

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

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