HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sandoval, A. Articles by Ogata, R. T. Search for Related Content PubMed PubMed Citation Articles by Sandoval, A. Articles by Ogata, R. T.

Distal Recognition Site for Classical Pathway Convertase Located in the C345C/Netrin Module of Complement Component C5¹

Torrey Pines Institute for Molecular Studies, San Diego, CA 92121

Previous studies focused on indels in the complement C345 protein family identified a number of potential protein-protein interaction sites in components C3 and C5. Here, one of these sites in C5, near the -chain C terminus, was examined by alanine-scanning mutagenesis at 16 of the 18 non-alanine residues in the sequence KEALQIKYNFSFRYIYPLD. Alanine substitutions affected activities in the highly variable manner characteristic of binding sites. Substitutions at the lysine or either phenylalanine residue in the central KYNFSF sequence had the greatest effects, yielding mutants with <20% of the normal activity. These three mutants were also resistant to the classical pathway (CP) C5 convertase, with sensitivities roughly proportional to their hemolytic activities, but had normal susceptibilities to the cobra venom factor (CVF)-dependent convertase. Synthetic peptide MGKEALQIKYNFS-NH₂ was found similarly to inhibit CP but not CVF convertase activation, and the effects of alanine substitutions in this peptide largely reflected those of the equivalent mutations in C5. These results indicate that residues KYNFSF form a novel, distal binding site for the CP, but not CVF convertase. This site lies 880 residues downstream of the convertase cleavage site within a module that has been independently named C345C and NTR; this module is found in diverse proteins including netrins and tissue inhibitors of metalloproteinases.

This article has been cited by other articles:

				J. Bramham, C.-T. Thai, D. C. Soares, D. Uhrin, R. T. Ogata, and P. N. Barlow Functional Insights from the Structure of the Multifunctional C345C Domain of C5 of Complement J. Biol. Chem., March 18, 2005; 280(11): 10636 - 10645. [Abstract] [Full Text] [PDF]

				M. A. Nunn, A. Sharma, G. C. Paesen, S. Adamson, O. Lissina, A. C. Willis, and P. A. Nuttall Complement Inhibitor of C5 Activation from the Soft Tick Ornithodoros moubata J. Immunol., February 15, 2005; 174(4): 2084 - 2091. [Abstract] [Full Text] [PDF]

				C.-T. Thai and R. T. Ogata Expression and Characterization of the C345C/NTR Domains of Complement Components C3 and C5 J. Immunol., December 15, 2003; 171(12): 6565 - 6573. [Abstract] [Full Text] [PDF]

				N. Rawal and M. K. Pangburn Formation of High Affinity C5 Convertase of the Classical Pathway of Complement J. Biol. Chem., October 3, 2003; 278(40): 38476 - 38483. [Abstract] [Full Text] [PDF]

				J. M. Inal and J. A. Schifferli Complement C2 Receptor Inhibitor Trispanning and the {beta}-Chain of C4 Share a Binding Site for Complement C2 J. Immunol., May 15, 2002; 168(10): 5213 - 5221. [Abstract] [Full Text] [PDF]

				N. Rawal and M. K. Pangburn Formation of High-Affinity C5 Convertases of the Alternative Pathway of Complement J. Immunol., February 15, 2001; 166(4): 2635 - 2642. [Abstract] [Full Text] [PDF]