PROSITE documentation PDOC51911

C2 Aida-type domain profile

The C2 domain, usually containing ~130 residues, is one of the most prevalent eukaryotic lipid-binding domains deployed in diverse functional contexts. Distinct versions of the C2 domain have been recognized, the classical C2 (see <PDOC00380>), the PI3K-type (see <PDOC51547>), the tensin-type (see <PDOC51181>), the B9-type (see <PDOC51381>), the DOCK-type (see <PDOC51650>), the NT-type (see <PDOC51840>) and the Aida-type. Despite their limited sequence similarity, all C2 domains contain at their core a compact β-sandwich composed of two four-stranded β sheets with highly variable inter-strand regions that might contain one or more α-helices. One feature that is highly conserved in the C2 domains is the pair of hydrophobic residues on the upper part of the β sheet, which are involved in imparting a curvature of the sheet that allows formation of a concave ligand-binding area. However, beyond the use of the β sheet in forming this concavity, the C2 domains are extremely divergent suggesting that different families might have optimized their interactions with membrane through divergent means. C2 domains have been shown to mediate specific associations with anionic phospholipids, in a Ca(2+)-dependent or Ca(2+)-independent manner, thereby participating in a variety of cellular processes, including cell signaling and vesicle trafficking. C2 domains interact with lipids primarily through two separate binding sites: the Ca(2+)-binding loops and the cationic β-groove. Calcium ion(s) binds to a cluster of aspartates located in three Ca(2+)-binding loops (CBR1, CBR2, and CBR3), which confer a positive charge on the C2 domain and therefore effectively mediate the interaction with phospholipids. Some other C2 domains present a cationic β-groove, the basic patch in the concave face of the β-sandwich, which is also involved in binding with anionic lipids, either, albeit with lower specificity [1,2].

The axin interaction dorsal-associated (Aida) protein was characterized in zebrafish as a protein that utilizes its C-terminal region to interact with axis formation inhibitor (Axin), which is a microtubule-interacting scaffold protein for several distinct signaling proteins in the Wnt cascade. The C-terminal region of the Aida protein is a distinct version of the C2 domain. In all proteins the Aida-type C2 domain is found in the C-terminal portion of the protein and it is combined with diverse domains related to cytoskeletal functions, e.g. EF hands (see <PDOC00018>), coiled coils, IQ calmodulin-binding motifs (see <PDOC50096>), ankyrin repeats (see <PDOC50088>) and myosin head motor domain (see <PDOC51456>), or with a second lipid-binding domain, e.g. the PH domain (see <PDOC50003>). The Aida-type C2 domain is found only in the metazoan, choanoflagellate, chromist and chlorophyte lineages [1,2].

The Aida-type C2 domain is organized into a predominantly β-strand globular fold (see <PDB:2QZ5>), composed of an antiparallel β-sandwich with two β-sheets, composed of strands β7, β8, β1, β4, an β3', and strands β3, β2, β5, β6 and β7', respectively. Three short α-helices, α1, α4, and α6, respectively connect β1 to β2, β4 to β5, and β6 to β7, and stabilize the conformation. The two-five-stranded sheets bend in the same direction. The association between Aida-type C2 domain and the membrane is not mediated via either of the above binding sites. Despite the overall structural resemblance, the Aida-type C2 domain does not harbor functional aspartates CBR loops for coordinating calcium ions and none of the positively charged residues are observed in the conventional β-groove. Instead, the Aida-type C2 domain associates with membranes via a novel extended positively charged surface - the basic loop connecting strands β7' and β8, and probably the positively CBR3 loop [2].

We developed a profile that covers the entire Aida-type C2 domain.