A Novel Predicted Calcium-Regulated Kinase Family Implicated in Neurological Disorders

The catalogues of protein kinases, the essential effectors of cellular signaling, have been charted in Metazoan genomes for a decade now. Yet, surprisingly, using bioinformatics tools, we predicted protein kinase structure for proteins coded by five related human genes and their Metazoan homologues, the FAM69 family. Analysis of three-dimensional structure models and conservation of the classic catalytic motifs of protein kinases present in four out of five human FAM69 proteins suggests they might have retained catalytic phosphotransferase activity. An EF-hand Ca2+-binding domain in FAM69A and FAM69B proteins, inserted within the structure of the kinase domain, suggests they may function as Ca2+-dependent kinases. The FAM69 genes, FAM69A, FAM69B, FAM69C, C3ORF58 (DIA1) and CXORF36 (DIA1R), are by large uncharacterised molecularly, yet linked to several neurological disorders in genetics studies. The C3ORF58 gene is found deleted in autism, and resides in the Golgi. Unusually high cysteine content and presence of signal peptides in some of the family members suggest that FAM69 proteins may be involved in phosphorylation of proteins in the secretory pathway and/or of extracellular proteins.作为细胞信号传导的关键效应因子，蛋白激酶（protein kinases）的谱系图谱已在后生动物（Metazoan）基因组中完成绘制十余年。但令人意外的是，借助生物信息学（bioinformatics）分析工具，我们针对5个相关人类基因及其后生动物同源物所编码的FAM69家族蛋白开展了蛋白激酶结构预测工作。通过对三维结构模型以及5个人类FAM69家族蛋白中4个所携带的经典蛋白激酶催化基序的保守性分析，我们推测这类蛋白可能仍保留催化磷酸转移酶（phosphotransferase）活性。FAM69A与FAM69B蛋白中存在一个插入于激酶结构域内部的EF手型钙离子结合（EF-hand Ca²⁺-binding）结构域，这表明它们可能作为钙离子依赖性激酶行使功能。FAM69家族基因包含FAM69A、FAM69B、FAM69C、C3ORF58（DIA1）以及CXORF36（DIA1R），目前在分子层面尚未得到充分表征，但遗传学研究已将其与多种神经系统疾病相关联。其中C3ORF58基因在自闭症患者中存在缺失现象，且其编码蛋白定位于高尔基体（Golgi）。部分家族成员具有异常高的半胱氨酸含量，且部分成员还携带信号肽（signal peptides），这提示FAM69家族蛋白可能参与分泌通路内以及/或细胞外蛋白的磷酸化修饰过程。