IQ motif and SEC7 domain-containing protein 1 (IQSEC1), also known as Arf-GEP100 or BRAG2, is a GEF (guanine nucleotide exchange factor) for Arf6 GTPase. In addition to Arf6, endogenous BRAG2 also activates the class II Arfs, Arf4 and Arf5. It acts at clathrin-coated pits to promote integrin internalization by activating Arf [, ]. It regulates phagocytosis of monocytic phagocytes in an ARF6-dependent process []and is involved in the apoptotic cell death of monocytic phagocytes [].
The IQSEC (IQ motif and SEC7 domain-containing protein), also called BRAG (Brefeldin A-resistant Arf-gunanine nucleotide exchange factor) family are a subset of Arf GEFs that have been shown to activate Arf6, which acts in the endocytic pathway to control the trafficking of a subset of cargo proteins including integrins. IQSEC family also have key roles in the function and organization of distinct excitatory and inhibitory synapses in the retina [, ]. The family consists of 3 members: IQSEC1 (also called BRAG2/GEP100), IQSEC2 (also called BRAG1), and IQSEC3 (also called SynArfGEF, BRAG3, or KIAA1110). IQSEC1 interacts with clathrin and modulates cell adhesion by regulating integrin surface expression and in addition to Arf6, it also activates the class II Arfs, Arf4 and Arf5 []. Mutations in IQSEC2 cause non-syndromic X-linked intellectual disability as well as reduced activation of Arf substrates (Arf1, Arf6) []. IQSEC3 regulates Arf6 at inhibitory synapses and associates with the dystrophin-associated glycoprotein complex and S-SCAM [].These IQSEC family members contain a IQ domain that may bind calmodulin, a PH domain that is thought to mediate membrane localization, and a SEC7 domain that can promote GEF activity on ARF []. The PH domain of BRAG2 has been shown to potentiate nucleotide exchange by binding to polyanionic membranes without marked phosphoinositides preference [].
