This domain occurs at the N terminus of Afi1 (Arf3-interacting protein 1), a protein necessary for vesicle trafficking in yeast. This domain is the interacting region of the protein which binds to Arf3. Afi1 is distributed asymmetrically at the plasma membrane and is required for polarized distribution of Arf3 but not of an Arf3 guanine nucleotide-exchange factor, Yel1p. However, Afi1 is not required for targeting of Arf3 or Yel1p to the plasma membrane. Afi1 functions as an Arf3 polarization-specific adapter and participates in development of polarity []. Although Arf3 is the homologue of human Arf6 it does not function in the same way, not being necessary for endocytosis or for mating factor receptor internalisation. In the S phase, however, it is concentrated at the plasma membrane of the emerging bud. Because of its polarized localisation and its critical function in the normal budding pattern of yeast, Arf3 is probably a regulator of vesicle trafficking, which is important for polarized growth.
Lsb5 plays important roles in membrane-trafficking events through association with the actin regulators, the yeast Wiskott-Aldrich syndrome protein (WASP) homologue Las17 and the cortical protein Sla1, the yeast Arf3 (orthologous with mammalian Arf6), and ubiquitin. Lsb5 contains an N-terminal VHS (Vps27p/Hrs/STAM)-domain and a GAT (GGA and TOM1) domain. In contrast to GGA proteins, Lsb5 harbours a C-terminal NPF (Asn-Pro-Phe) motif, but does not have either a GAE (gamma-adaptin ear homology) domain or a clathrin-binding motif [, , ].
Lsb5 plays important roles in membrane-trafficking events through association with the actin regulators, the yeast Wiskott-Aldrich syndrome protein (WASP) homologue Las17 and the cortical protein Sla1, the yeast Arf3 (orthologous with mammalian Arf6), and ubiquitin. Lsb5 contains an N-terminal VHS (Vps27p/Hrs/STAM)-domain and a GAT (GGA and TOM1) domain. In contrast to GGA proteins, Lsb5 harbours a C-terminal NPF (Asn-Pro-Phe) motif, but does not have either a GAE (gamma-adaptin ear homology) domain or a clathrin-binding motif [, , ].This entry represents the GAT domain found in Lsb5.
Arf6 (ADP ribosylation factor 6) proteins localize to the plasma membrane, where they perform a wide variety of functions. In its active, GTP-bound form, Arf6 is involved in cell spreading, Rac-induced formation of plasma membrane ruffles, cell migration, wound healing, and Fc-mediated phagocytosis. Arf6 appears to change the actin structure at the plasma membrane by activating Rac, a Rho family protein involved in membrane ruffling. Arf6 is required for and enhances Rac formation of ruffles. Arf6 can regulate dendritic branching in hippocampal neurons, and in yeast it localizes to the growing bud, where it plays a role in polarized growth and bud site selection. In leukocytes, Arf6 is required for chemokine-stimulated migration across endothelial cells. Arf6 also plays a role in down-regulation of beta2-adrenergic receptors and luteinizing hormone receptors by facilitating the release of sequestered arrestin to allow endocytosis. Arf6 is believed to function at multiple sites on the plasma membrane through interaction with a specific set of GEFs, GAPs, and effectors []. Arf6 has been implicated in breast cancer and melanoma cell invasion [, ], and in actin remodelling at the invasion site of Chlamydia infection [].It's worth noting that the Arf6 homologue in Saccharomyces cerevisiae is known as Arf3 [].
Arf GTPases are involved in the formation of coated carrier vesicles by recruiting coat proteins. This entry includes Arf1, Arf2, Arf3, Arf4, Arf5, and related proteins. Each contains an N-terminal myristoylated amphipathic helix that is folded into the protein in the GDP-bound state. GDP/GTP exchange exposes the helix, which anchors to the membrane. Following GTP hydrolysis, the helix dissociates from the membrane and folds back into the protein. A general feature of Arf1-5 signaling may be the cooperation of two Arfs at the same site. Arfs1-5 are generally considered to be interchangeable in function and location, but some specific functions have been assigned []. Arf1 localizes to the early/cis-Golgi, where it is activated by GBF1 and recruits the coat protein COPI. It also localizes to the trans-Golgi network (TGN), where it is activated by BIG1/BIG2 and recruits the AP1, AP3, AP4, and GGA proteins []. Humans, but not rodents and other lower eukaryotes, lack Arf2. Human Arf3 shares 96% sequence identity with Arf1 and is believed to generally function interchangeably with Arf1. Human Arf4 in the activated (GTP-bound) state has been shown to interact with the cytoplasmic domain of epidermal growth factor receptor (EGFR) and mediate the EGF-dependent activation of phospholipase D2 (PLD2), leading to activation of the activator protein 1 (AP-1) transcription factor []. Arf4 has also been shown to recognise the C-terminal sorting signal of rhodopsin and regulate its incorporation into specialised post-Golgi rhodopsin transport carriers (RTCs) []. There is some evidence that Arf5 functions at the early-Golgi and the trans-Golgi to affect Golgi-associated alpha-adaptin homology Arf-binding proteins (GGAs) [].
