title: A membrane proximal helix in the cytosolic domain of the human APP interacting protein LR11/SorLA deforms liposomes.
abstract: Over the last decade, compelling evidence has linked the development of Alzheimer's disease (AD) to defective intracellular trafficking of the amyloid precursor protein (APP). Faulty APP trafficking results in an overproduction of Aβ peptides, which is generally agreed to be the primary cause of AD-related pathogenesis. LR11 (SorLA), a type I transmembrane sorting receptor, has emerged as a key regulator of APP trafficking and processing. It directly interacts with APP and diverts it away from amyloidogenic processing. The 54-residue cytosolic domain of LR11 is essential for its proper intracellular localization and trafficking which, in turn, determines the fate of APP. Here, we have found a surprising membrane-proximal amphipathic helix in the cytosolic domain of LR11. Moreover, a peptide corresponding to this region folds into an α-helical structure in the presence of liposomes and transforms liposomes to small vesicles and tubule-like particles. We postulate that this amphipathic helix may contribute to the dynamic remodeling of membrane structure and facilitate LR11 intracellular transport.
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, Pennsylvania State University, Hershey, PA 17033, USA.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Gill
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, Pennsylvania State University, Hershey, PA 17033, USA.
authors.forename: Xingsheng
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, Pennsylvania State University, Hershey, PA 17033, USA. Electronic address: ftian@psu.edu.
authors.forename: Fang
authors.initials: F
authors.lastname: Tian
mesh_terms: D000595:Amino Acid Sequence; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry*; D003600:Cytosol / Q000737:chemistry; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000737:chemistry*; D008081:Liposomes / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D026901:Membrane Transport Proteins / Q000737:chemistry*; D008969:Molecular Sequence Data; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D026502:LDL-Receptor Related Proteins; D008081:Liposomes; D026901:Membrane Transport Proteins; C102582:SORL1 protein, human
keywords: Alzheimer's disease; Amphipathic helix; Amyloid precursor protein (APP); LR11; Membrane curvature; SorLA