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. 2013 Feb 15;126(Pt 4):989-98.
doi: 10.1242/jcs.117804. Epub 2012 Dec 21.

Identification of a novel motif that affects the conformation and activity of the MARCH1 E3 ubiquitin ligase

Marie-Claude Bourgeois-Daigneault  1 , Jacques Thibodeau
Affiliations

Identification of a novel motif that affects the conformation and activity of the MARCH1 E3 ubiquitin ligase

Marie-Claude Bourgeois-Daigneault et al. J Cell Sci. .

Abstract

MARCH1, a member of the membrane-associated RING-CH family of E3 ubiquitin ligases, regulates antigen presentation by downregulating the cell surface expression of Major Histocompatibility Complex class II and CD86 molecules. MARCH1 is a transmembrane protein that exposes both its N- and C-terminus to the cytoplasm. We have conducted a structure-function analysis of its two cytoplasmic tails to gain insights into the trafficking of MARCH1 in the endocytic pathway. Fusion of the N-terminal portion of MARCH1 to a type II transmembrane reporter molecule revealed that this cytoplasmic tail contains endosomal sorting motifs. The C-terminal domain also appears to contain intracellular sorting signals because it reduced surface expression of a type I transmembrane reporter molecule. Mutation of the two putative C-terminal tyrosine-based sorting signals did not affect the activity of human MARCH1; however, it did reduce its incorporation into exosomes. Moreover, site-directed mutagenesis pointed to a functional C-terminal 221VQNC224 sequence that affects the spatial organization of the two cytoplasmic regions. This motif is also found in other RING-type E3 ubiquitin ligases, such as parkin. Altogether, these findings highlight the complex regulation of MARCH1 trafficking in the endocytic pathway as well as the intricate interactions between its cytoplasmic tails.

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