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A Short Consensus Repeat-Containing Complement Regulatory Protein of Lamprey That Participates in Cleavage of Lamprey Complement 3¹

Yuko Kimura^2,*, Naokazu Inoue^2,3,*, Aya Fukui^4,*, Hiroyuki Oshiumi^5,*, Misako Matsumoto^*, Mayumi Nonaka, Shigeru Kuratani, Teizo Fujita, Masaru Nonaka and Tsukasa Seya^6,*

^* Department of Immunology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan; Department of Biological Sciences, Graduate School of Science, University of Tokyo, Tokyo, Japan; Department of Embryology, RIKEN, Kobe, Japan; and Department of Biochemistry, Fukushima Medical University, Fukushima, Japan

The prototype of the short consensus repeat (SCR)-containing C regulatory protein is of interest in view of its evolutionary significance with regard to the origin of the C regulatory system. Lamprey is an agnathan fish that belongs to the lowest class of vertebrates. Because it does not possess lymphocytes, it lacks Ig and consequently the classical C pathway. We identified an SCR-containing C regulatory protein from the lamprey. The primary structure predicted from the cDNA sequence showed that this is a secretary protein consisting of eight SCRs. This framework is similar to the -chain of C4b-binding protein (C4bp). SCR2 and -3 of human C4bp are essential for C4b inactivation, and this region is fairly well conserved in the lamprey protein. However, the other SCRs of this protein are similar to those of other human C regulatory proteins. The lamprey protein binds to the previously reported lamprey C3b/C3bi deposited on yeast and cleaves lamprey C3b-like C3 together with a putative serum protease. The scheme resembles the C regulatory system of mammals, where factor I and its cofactor inactivate C3b. Unlike human cofactors, the lamprey protein requires divalent cations for C3b-like C3 cleavage. Its artificial membrane-anchored form protects host cells from lamprey C attack via the lectin pathway. Thus, the target of this protein appears to be C3b and/or its family. We named this protein Lacrep, the lamprey C regulatory protein. Lacrep is a member of SCR-containing C regulators, the first of its kind identified in the lowest vertebrates.

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