title: Presenilin 2 interacts with sorcin, a modulator of the ryanodine receptor.
abstract: Perturbed Ca(2+) homeostasis is a common molecular consequence of familial Alzheimer's disease-linked presenilin mutations. We report here the molecular interaction of the large hydrophilic loop region of presenilin 2 (PS2) with sorcin, a penta-EF-hand Ca(2+)-binding protein that serves as a modulator of the ryanodine receptor intracellular Ca(2+) channel. The association of endogenous sorcin and PS2 was demonstrated in cultured cells and human brain tissues. Membrane-associated sorcin and a subset of the functional PS2 complexes were co-localized to a novel subcellular fraction that is distinctively positive for calcineurin B. Sorcin was found to interact with PS2 endoproteolytic fragments but not full-length PS2, and the sorcin/PS2 interaction was greatly enhanced by treatment with the Ca(2+) ionophore A23187. Our findings reveal a molecular link between PS2 and intracellular Ca(2+) channels (i.e. ryanodine receptor) and substantiate normal and/or pathological roles of PS2 in intracellular Ca(2+) homeostasis.
authors.affiliation: Genetics and Aging Research Unit, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
authors.forename: E
authors.initials: E
authors.lastname: Pack-Chung
authors.forename: M B
authors.initials: MB
authors.lastname: Meyers
authors.forename: W P
authors.initials: WP
authors.lastname: Pettingell
authors.forename: R D
authors.initials: RD
authors.lastname: Moir
authors.forename: A M
authors.initials: AM
authors.lastname: Brownawell
authors.forename: I
authors.initials: I
authors.lastname: Cheng
authors.forename: R E
authors.initials: RE
authors.lastname: Tanzi
authors.forename: T W
authors.initials: TW
authors.lastname: Kim
mesh_terms: D000595:Amino Acid Sequence; D001692:Biological Transport; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D008969:Molecular Sequence Data; D053766:Presenilin-2; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D013347:Subcellular Fractions / Q000378:metabolism
chemical_list: D002135:Calcium-Binding Proteins; D008565:Membrane Proteins; C508861:PSEN2 protein, human; D053766:Presenilin-2; D019837:Ryanodine Receptor Calcium Release Channel; C503113:SRI protein, human; D002118:Calcium