C2 domain in the Active BCR (Breakpoint cluster region) Related proteinThe ABR protein is similar to the breakpoint cluster region protein. It has homology to guanine nucleotide exchange proteins and GTPase-activating proteins (GAPs). ABR is expressed primarily in the brain, but also includes non-neuronal tissues such as the heart. It has been associated with human diseases such as Miller-Dieker syndrome in which mental retardation and malformations of the heart are present. ABR contains a RhoGEF domain and a PH-like domain upstream of its C2 domain and a RhoGAP domain downstream of this domain. A few members also contain a Bcr-Abl oncoprotein oligomerization domain at the very N-terminal end. Splice variants of ABR have been identified. ABR is found in a wide variety of organisms including chimpanzee, dog, mouse, rat, fruit fly, and mosquito. The C2 domain was first identified in PKC. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions.