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Mapping the active site of CD59.

Yu J, Abagyan R, Dong S, Gilbert A, Nussenzweig V, Tomlinson S - J. Exp. Med. (1997)

Bottom Line: CD59 functions by binding to C8 and/or C9 in the nascent MAC and interfering with C9 membrane insertion and polymerization.We present data obtained from a combination of molecular modeling and mutagenesis techniques, which together indicate that the active site of CD59 is located in the vicinity of a hydrophobic groove on the face of the molecule opposite to a "hydrophobic strip" suggested earlier.In addition, removal of the single N-linked glycosylation site at Asn18 of CD59 resulted in an enhancement of complement inhibitory activity.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, New York University Medical Center, New York 10016, USA.

ABSTRACT
CD59 is a widely distributed membrane-bound inhibitor of the cytolytic membrane attack complex (MAC) of complement. This small (77 amino acid) glycoprotein is a member of the Ly6 superfamily of proteins and is important in protecting host cells from the lytic and proinflammatory activity of the MAC. CD59 functions by binding to C8 and/or C9 in the nascent MAC and interfering with C9 membrane insertion and polymerization. We present data obtained from a combination of molecular modeling and mutagenesis techniques, which together indicate that the active site of CD59 is located in the vicinity of a hydrophobic groove on the face of the molecule opposite to a "hydrophobic strip" suggested earlier. In addition, removal of the single N-linked glycosylation site at Asn18 of CD59 resulted in an enhancement of complement inhibitory activity.

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Related in: MedlinePlus

CD59 and Ly6E sequence comparison. Mature protein sequences are shown with  the conserved cysteine residues  marked (:). The amino acids  forming the surface loops and  helix of CD59 are shown. The  COOH-terminal end of mature  Ly6E is predicted.
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Figure 1: CD59 and Ly6E sequence comparison. Mature protein sequences are shown with the conserved cysteine residues marked (:). The amino acids forming the surface loops and helix of CD59 are shown. The COOH-terminal end of mature Ly6E is predicted.

Mentions: CD59 belongs to the Ly6 superfamily of proteins which includes functional CD59 analogues from other species, snake venom neurotoxins, urokinase-type plasminogen activator receptor and murine Ly6 differentiation antigens (17). Mouse Ly6E antigen (18) is a structural but not functional analogue of CD59 (see Fig. 1). In the approach reported here, functionally important regions of CD59 were determined by replacing regions of Ly6E with corresponding regions from CD59 and assaying expressed chimeric proteins for activity. The active site was then further defined by a series of site-specific mutations, selected as a result of comparing evolutionary conserved residues and modeling of the molecular surface of CD59.


Mapping the active site of CD59.

Yu J, Abagyan R, Dong S, Gilbert A, Nussenzweig V, Tomlinson S - J. Exp. Med. (1997)

CD59 and Ly6E sequence comparison. Mature protein sequences are shown with  the conserved cysteine residues  marked (:). The amino acids  forming the surface loops and  helix of CD59 are shown. The  COOH-terminal end of mature  Ly6E is predicted.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2196154&req=5

Figure 1: CD59 and Ly6E sequence comparison. Mature protein sequences are shown with the conserved cysteine residues marked (:). The amino acids forming the surface loops and helix of CD59 are shown. The COOH-terminal end of mature Ly6E is predicted.
Mentions: CD59 belongs to the Ly6 superfamily of proteins which includes functional CD59 analogues from other species, snake venom neurotoxins, urokinase-type plasminogen activator receptor and murine Ly6 differentiation antigens (17). Mouse Ly6E antigen (18) is a structural but not functional analogue of CD59 (see Fig. 1). In the approach reported here, functionally important regions of CD59 were determined by replacing regions of Ly6E with corresponding regions from CD59 and assaying expressed chimeric proteins for activity. The active site was then further defined by a series of site-specific mutations, selected as a result of comparing evolutionary conserved residues and modeling of the molecular surface of CD59.

Bottom Line: CD59 functions by binding to C8 and/or C9 in the nascent MAC and interfering with C9 membrane insertion and polymerization.We present data obtained from a combination of molecular modeling and mutagenesis techniques, which together indicate that the active site of CD59 is located in the vicinity of a hydrophobic groove on the face of the molecule opposite to a "hydrophobic strip" suggested earlier.In addition, removal of the single N-linked glycosylation site at Asn18 of CD59 resulted in an enhancement of complement inhibitory activity.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, New York University Medical Center, New York 10016, USA.

ABSTRACT
CD59 is a widely distributed membrane-bound inhibitor of the cytolytic membrane attack complex (MAC) of complement. This small (77 amino acid) glycoprotein is a member of the Ly6 superfamily of proteins and is important in protecting host cells from the lytic and proinflammatory activity of the MAC. CD59 functions by binding to C8 and/or C9 in the nascent MAC and interfering with C9 membrane insertion and polymerization. We present data obtained from a combination of molecular modeling and mutagenesis techniques, which together indicate that the active site of CD59 is located in the vicinity of a hydrophobic groove on the face of the molecule opposite to a "hydrophobic strip" suggested earlier. In addition, removal of the single N-linked glycosylation site at Asn18 of CD59 resulted in an enhancement of complement inhibitory activity.

Show MeSH
Related in: MedlinePlus