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Publication Abstract from PubMed

Tyrosine-based signals fitting the YXXPhi motif mediate sorting of transmembrane proteins to endosomes, lysosomes, the basolateral plasma membrane of polarized epithelial cells and the somatodendritic domain of neurons through interactions with the homologous mu1, mu2, mu3 and mu4 subunits of the corresponding AP-1, AP-2, AP-3 and AP-4 complexes. Previous X-ray crystallographic analyses identified distinct binding sites for YXXPhi signals on mu2 and mu4, which were located on opposite faces of the proteins. To elucidate the mode of recognition of YXXPhi signals by other members of the mu family, we solved the crystal structure at 1.85 Angstrom resolution of the C-terminal domain of the mu3 subunit of AP-3 (isoform A) in complex with a peptide encoding a YXXPhi signal (SDYQRL) from the trans-Golgi network protein TGN38. The mu3A C-terminal domain consists of an immunoglobulin-like beta-sandwich organized into two subdomains, A and B. The YXXPhi signal binds in an extended conformation to a site on mu3A subdomain A, at a location similar to the YXXPhibinding site on mu2 but not mu4. The binding sites on mu3A and mu2 exhibit similarities and differences that account for the ability of both proteins to bind distinct sets of YXXPhi signals. Biochemical analyses confirm the identification of the mu3A site and show that this protein binds YXXPhi signals with 14-19 muM affinity. The surface electrostatic potential of mu3A is less basic than that of mu2, in part explaining the association of AP-3 with intracellular membranes having less acidic phosphoinositides.

Structural Basis for the Recognition of Tyrosine-based Sorting Signals by the Mu3A Subunit of the AP-3 Adaptor Complex.,Mardones GA, Burgos PV, Lin Y, Kloer DP, Magadan JG, Hurley JH, Bonifacino JS J Biol Chem. 2013 Feb 12. PMID:23404500^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.