Kraus Damian M, Elliott Gary S, Chute Hilary, Horan Thomas, Pfenninger Karl H, Sanford Staci D, Foster Stephen, Scully Sheila, Welcher Andrew A, Holers V Michael
Division of Rheumatology, University of Colorado Health Sciences Center, Denver, 80262, USA.
J Immunol. 2006 Apr 1;176(7):4419-30. doi: 10.4049/jimmunol.176.7.4419.
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.
在本研究中，我们描述了一种新型多结构域补体调节蛋白的鉴定及其体外功能活性。该蛋白是基于其与补体激活调节因子（RCA）基因家族中含短共有重复序列（SCR）的蛋白的同源性而发现的。大鼠cDNA编码一种预测分子量为388 kDa的蛋白，该蛋白由14个N端CUB结构域组成，这些结构域被一个SCR彼此隔开，随后是15个串联的SCR结构域、一个跨膜结构域和一个短的胞质尾。该蛋白是人类功能未知的CUB和寿司多结构域1（CSMD1）蛋白的同源物。采用一种包含两个C端CUB-SCR结构域和12个串联SCR重复序列的克隆策略来制备可溶性大鼠CSMD1蛋白。该蛋白以与大鼠Crry类似的方式阻断经典补体途径的激活，但不阻断替代途径的激活。通过原位杂交分析CSMD1 mRNA表达以及对神经元进行免疫标记表明，合成的主要部位是发育中的中枢神经系统和上皮组织。特别重要的是，CSMD1在神经生长锥（即生长中神经元的阿米巴样前缘）中富集。这些结果表明，CSMD1可能是发育中中枢神经系统补体激活和炎症的重要调节因子，并且它可能在生长锥功能方面也发挥作用。
