A Corresponding Tyrosine Residue in the C2/Factor B Type A Domain Is a Hot Spot in the Decay Acceleration of the Complement C3 Convertases

Lisa A. Kuttner-Kondo, Megan P. Dybvig, Lynne M. Mitchell, Nasima Muqim, John P. Atkinson, M. Edward Medof, Dennis E. Hourcade

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

The cleavage of C3 by the C3 convertases (C3bBb and C4b2a) determines whether complement activation proceeds. Dissociation (decay acceleration) of these central enzymes by the regulators decay-accelerating factor (DAF), complement receptor 1 (CR1), factor H, and C4-binding protein (C4BP) controls their function. In a previous investigation, we obtained evidence implicating the α4/5 region of the type A domain of Bb (especially Tyr338) in decay acceleration of C3bBb and proposed this site as a potential interaction point with DAF and long homologous repeat A of CR1. Because portions of only two DAF complement control protein domains (CCPs), CCP2 and CCP3, are necessary to mediate its decay of the CP C3 convertase (as opposed to portions of at least three CCPs in all other cases, e.g. CCPs 1-3 of CR1), DAF/C4b2a provides the simplest structural model for this reaction. Therefore, we examined the importance of the C2 α4/5 site on decay acceleration of C4b2a. Functional C4b2a complexes made with the C2 Y327A mutant, the C2 homolog to factor B Y338A, were highly resistant to DAF, C4BP, and long homologous repeat A of CR1, whereas C2 substitutions in two nearby residues (N324A and L328A) resulted in partial resistance. Our new findings indicate that the α4/5 region of C2a is critical to decay acceleration mediated by DAF, C4BP, and CR1 and suggest that decay acceleration of C4b2a and C3bBb requires interaction of the convertase α4/5 region with a CCP2/CCP3 site of DAF or structurally homologous sites of CR1 and C4BP.

Original languageEnglish
Pages (from-to)52386-52391
Number of pages6
JournalJournal of Biological Chemistry
Volume278
Issue number52
DOIs
StatePublished - Dec 26 2003

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