title: The C-terminal C1 cassette of the N -methyl-D-aspartate receptor 1 subunit contains a bi-partite nuclear localization sequence.
abstract: The N -methyl-D-aspartate receptor (NMDAR) is a multimeric transmembrane protein composed of at least two subunits. One subunit, NR1, is derived from a single gene and can be subdivided into three regions: the N-terminal extracellular domain, the transmembrane regions, and the C-terminal intracellular domain. The N-terminal domain is responsible for Mg2+ metal ion binding and channel activity, while the transmembrane domains are important for ion channel formation. The intracellular C-terminal domain is involved in regulating receptor activity and subcellular localization. Our recent experiments indicated that the intracellular C-terminal domain, when expressed independently, localizes almost exclusively in the nucleus. An examination of the amino acid sequence reveals the presence of a putative nuclear localization sequence (NLS) in the C1 cassette of the NR1 intracellular C-terminus. Using an expression vector designed to test whether a putative NLS sequence is a valid, functional NLS, we have demonstrated that a bi-partite NLS does in fact exist within the NR1-1 C-terminus. Computer algorithms identified a putative helix-loop-helix motif that spanned the C0C1 cassettes of the C-terminus. These data suggest that the NR1 subunit may represent another member of a family of transmembrane proteins that undergo intramembrane proteolysis, releasing a cytosolic peptide that is actively translocated to the nucleus leading to alterations in gene regulation.
authors.affiliation: The Gene Therapy and Molecular Virology Group and the Neurodegeneration Group, The John P. Robarts Research Institute, London, Ontario, Canada.
authors.forename: K D
authors.initials: KD
authors.lastname: Holmes
authors.forename: P
authors.initials: P
authors.lastname: Mattar
authors.forename: D R
authors.initials: DR
authors.lastname: Marsh
authors.forename: V
authors.initials: V
authors.lastname: Jordan
authors.forename: L C
authors.initials: LC
authors.lastname: Weaver
authors.forename: G A
authors.initials: GA
authors.lastname: Dekaban
mesh_terms: D000595:Amino Acid Sequence / Q000235:genetics; D000818:Animals; D002457:Cell Extracts / Q000737:chemistry; D002460:Cell Line / Q000737:chemistry; D002467:Cell Nucleus / Q000378:metabolism; D002999:Clone Cells; D008969:Molecular Sequence Data; D019913:Nuclear Localization Signals / Q000235:genetics; D016716:PC12 Cells / Q000737:chemistry; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary / Q000235:genetics; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism* / Q000502:physiology; D011994:Recombinant Proteins / Q000378:metabolism
chemical_list: D002457:Cell Extracts; D019913:Nuclear Localization Signals; D016194:Receptors, N-Methyl-D-Aspartate; D011994:Recombinant Proteins; C120997:NR2A NMDA receptor