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CSMD1 Is a Novel Multiple Domain Complement-Regulatory Protein Highly Expressed in the Central Nervous System and Epithelial Tissues¹

Damian M. Kraus^*, Gary S. Elliott, Hilary Chute, Thomas Horan, Karl H. Pfenninger, Staci D. Sanford, Stephen Foster, Sheila Scully, Andrew A. Welcher and V. Michael Holers^2,*

^* Division of Rheumatology, University of Colorado Health Sciences Center, Denver, CO 80262; Amgen, Thousand Oaks, CA 91320; and Departments of Pediatrics and of Cell and Developmental Biology, University of Colorado Health Sciences Center, Aurora, CO 80045

In this study, we describe the identification and in vitro functional activity of a novel multiple domain complement regulatory protein discovered based on its homology to short consensus repeat (SCR)-containing proteins of the regulators of complement activation (RCA) gene family. The rat cDNA encodes a predicted 388-kDa protein consisting of 14 N-terminal CUB domains that are separated from each other by a SCR followed by 15 tandem SCR domains, a transmembrane domain, and a short cytoplasmic tail. This protein is the homolog of the human protein of unknown function called the CUB and sushi multiple domains 1 (CSMD1) protein. A cloning strategy that incorporates the two C-terminal CUB-SCR domains and 12 of the tandem SCR repeats was used to produce a soluble rat CSMD1 protein. This protein blocked classical complement pathway activation in a comparable fashion with rat Crry but did not block alternative pathway activation. Analysis of CSMD1 mRNA expression by in situ hybridization and immunolabeling of neurons indicates that the primary sites of synthesis are the developing CNS and epithelial tissues. Of particular significance is the enrichment of CSMD1 in the nerve growth cone, the amoeboid-leading edge of the growing neuron. These results suggest that CSMD1 may be an important regulator of complement activation and inflammation in the developing CNS, and that it may also play a role in the context of growth cone function.

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The JI 2006 176: 3851-3852. [Full Text]  

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