title: C-terminus of progranulin interacts with the beta-propeller region of sortilin to regulate progranulin trafficking.
abstract: Progranulin haplo-insufficiency is a main cause of frontotemporal lobar degeneration (FTLD) with TDP-43 aggregates. Previous studies have shown that sortilin regulates progranulin trafficking and is a main determinant of progranulin level in the brain. In this study, we mapped the binding site between progranulin and sortilin. Progranulin binds to the beta-propeller region of sortilin through its C-terminal tail. The C-terminal progranulin fragment is fully sufficient for sortilin binding and progranulin C-terminal peptide displaces progranulin binding to sortilin. Deletion of the last 3 residues of progranulin (QLL) abolishes its binding to sortilin and also sortilin dependent regulation of progranulin trafficking. Since progranulin haplo-insufficiency results in FTLD, these results may provide important insights into future studies of progranulin trafficking and signaling and progranulin based therapy for FTLD.
authors.affiliation: Department of Molecular Biology and Genetics, Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, New York, United States of America.
authors.forename: Yanqiu
authors.initials: Y
authors.lastname: Zheng
authors.forename: Owen A
authors.initials: OA
authors.lastname: Brady
authors.forename: Peter S
authors.initials: PS
authors.lastname: Meng
authors.forename: Yuxin
authors.initials: Y
authors.lastname: Mao
authors.forename: Fenghua
authors.initials: F
authors.lastname: Hu
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000737:chemistry / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D000077153:Progranulins; D011485:Protein Binding; D021381:Protein Transport; D017386:Sequence Homology, Amino Acid; D000099183:Sortilin
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; D000099183:Sortilin; C492314:GRN protein, human