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In vertebrates, the Attractin (Atrn) transmembrane protein family is comprised of ATRN, Attractin-like 1 (ATRNL1) and Multiple epidermal growth factor-like domain 8 (MEGF8) proteins, which contain an extensive extracellular domain with numerous protein interaction motifs and a highly conserved intracellular MASRPF motif (Fig. 1A and B) (Walker et al., 2007). Common to all three paralogs is that they have a strong phenotypic overlap with E3-ligase Mahogunin ring finger 1 (Mgrn1), due to regulation of the same G-protein coupled receptors (GPCRs) as Mgrn1. For example, rodent Atrn and Mgrn1 negatively regulate signaling melanocortin receptors MCR1 and MCR4 by promoting their endolysosomal trafficking. Thus, loss of function mutations in Atrn or Mgrn1 suppress the pigmentation and obesity phenotypes of MCR1/4 antagonist gain of function mutants (Barsh et al., 2002; He et al., 2003; Nagle et al., 1999). Loss of function of Megf8 and Mgrn1 mutants exhibit common developmental phenotypes (Aune et al., 2008; Cota et al., 2006; Zhang et al., 2009) and both proteins were identified as negative regulators of the GPCR Smoothened in mice (Pusapati et al., 2018). Most recently it was shown in vitro that Mgrn1 and Megf8 co-immunoprecipitate in a MASRPF motif-dependent manner, and this association is required for Mgrn1 to mediate membrane-tethered ubiquitination to modulate the signaling strength of Hedgehog morphogens in mice (Kong et al., 2020). |
