Source: http://cegg.unige.ch/insecta/immunodb/

CLIPs: CLIP-Domain Serine Proteases
Summary

Haobo Jiang(1), Zhen Zhou(1), and Mike Kanost(2) 

1. Department of Entomology and Plant Pathology, Oklahoma State University, USA
2. Department of Biochemistry, Kansas State University, Manhattan, KS 66506, USA 

Serine proteases containing one or more clip domains [Jiang & Kanost 2000] function in extracellular pathways that regulate some immune responses of insects. The CLIP proteases represent a protein architecture apparently unique to arthropods, and they form large gene families in the insect species studies so far [Christophides et al. 2002; Ross et al. 2003]. Infections can stimulate activation of CLIP protease zymogens present in hemolymph, resulting in proteolytic activation of prophenoloxidases (PPOs) [Kanost et al. 2004; Tang et al. 2006] or activation of the Toll-ligand sp�tzle [Jang et al. 2006; Kambris et al. 2006]. The latter also occurs to regulate development of dorsal/ventral pattern in Dm embryos. Some members of the CLIP family contain a protease domain in which one or more of the catalytic triad residues has mutated such that they are no longer possess proteolytic activity. Such serine protease homologs (SPH) can function as cofactors required for PPO activation by an active CLIP protease [Yu et al. 2003], and they can also negatively regulate the melanization response [Volz et al. 2006]. The CLIP family in Aa is quite large, with 68 genes (compared with 45 in Dm and 54 in Ag), including at least 12 SPHs and 5 genes predicted to encode dual protease and SPH domains. Phylogenetic analysis of the sequences reveals five main subfamilies, including previously described groups A-D [Christophides et al. 2002] and a new subfamily E containing previously unannotated AgCLIPs. Nearly all of the CLIPA and CLIPE genes encode SPHs, whereas the CLIPB, CLIPC, and CLIPD groups are predominantly proteases with intact catalytic triads. Subfamily B is the largest, and its sequences are most similar to the clip proteases that can activate sp�tzle (Easter and SPE) and those known from studies in lepidopteran and coleopteran species to directly activate PPO. Members of subfamily C with known functions include DmSnake (embryonic dorsal/ventral pattern) and DmPersephone (involvement in innate immune Toll pathway). Functions of CLIP proteases in subfamily D have not yet been identified. Although CLIP-domain sequences are poorly conserved, the CLIP-domain sequences from active CLIP-proteases in Dm fall into three groups based on distance between conserved Cys residues and on a few other conserved residues [Ross et al. 2003]. There is a very good correlation between branches of the CLIP tree based on alignment of only the protease domain and the type of associated clip domain. Subfamily C is associated with clip domain type 1a, subfamily D with clip domain type 1b, and subfamily B with clip domain type 2. Considering that a function is known for only a few CLIP proteases in any insect species, the complexity of this gene family in Aa presents a challenging and exciting prospect for future experimental studies of their roles in immune responses.