![]() ![]() N-terminal BAR, N-BAR, and EFC/F-BAR domains are found in proteins that regulate membrane trafficking events by inducing membrane tubulation (reviewed in Itoh and De Camilli, 2006). Adaptors from each known μHD-containing protein family (μ-subunits, stonins, δ-COP) bind to transmembrane cargo through the μHD ( Jung et al, 2007). This led to the discovery of the Golgi-localized γ-subunit ear containing ARF-binding adaptor proteins, and supported trafficking functions for the stonins ( Andrews et al, 1996 Hirst et al, 2000). Exhaustive genome mining of complete model organism genomes identified proteins with similarity to key domains of the AP complex subunits ( Boehm and Bonifacino, 2001). The first cargo-binding subunit found was the C-terminal μ homology domain (μHD) of the μ2 subunit of AP-2 the μHD binds to YxxΦ (Tyr-any residue-any residue-bulky hydrophobic residue) peptide motifs in the cytoplasmic tails of transmembrane cargo proteins ( Ohno et al, 1995 Owen and Evans, 1998). The Golgi/endosome-associated AP-1 and PM-associated AP-2 complexes were the first such factors to be identified, each composed of four non-identical subunits. The in vivo assembly of clathrin triskelions into coats that surround cargo-loaded membrane vesicles requires assembly factors ( Smythe et al, 1992). ![]() However, the wide array of plasma membrane (PM) protein cargo, and the relatively few with assigned adaptor proteins in the literature, suggests that there are more adaptor proteins that have yet to be identified. The study of these proteins’ contributions to CCV formation has greatly accelerated the understanding of the mechanisms of endocytosis. More than fifty proteins contribute to the formation of clathrin-coated vesicles (CCV), most of which are conserved from yeast to human ( Engqvist-Goldstein and Drubin, 2003). These and other data suggest a model in which the muniscins provide a combined adaptor/membrane-tubulation activity that is important for regulating endocytosis.Įndocytosis is critical for maintaining cell homeostasis and regulating signal transduction and nutrient uptake ( Sorkin and von Zastrow, 2002). The transmembrane protein Mid2, earlier implicated in polarized Rho1 signalling, was identified as a cargo of the yeast adaptor protein. The μHD domain has conserved interactions with the endocytic adaptor/scaffold Ede1/eps15, which influences muniscin localization. In vitro and in vivo assays confirmed membrane-tubulation activity for muniscin EFC/F-BAR domains. Solving the structures of yeast muniscin domains confirmed the unique combination of an N-terminal domain homologous to the crescent-shaped membrane-tubulating EFC/F-BAR domains and a C-terminal domain homologous to cargo-binding μ homology domains (μHDs). We report the identification of the muniscin family of endocytic adaptors that is conserved from yeast to human beings. Internalization of diverse transmembrane cargos from the plasma membrane requires a similarly diverse array of specialized adaptors, yet only a few adaptors have been characterized. ![]()
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