title: Structural basis of E2-25K/UBB+1 interaction leading to proteasome inhibition and neurotoxicity.
abstract: E2-25K/Hip2 is an unusual ubiquitin-conjugating enzyme that interacts with the frameshift mutant of ubiquitin B (UBB(+1)) and has been identified as a crucial factor regulating amyloid-β neurotoxicity. To study the structural basis of the neurotoxicity mediated by the E2-25K-UBB(+1) interaction, we determined the three-dimensional structures of UBB(+1), E2-25K and the E2-25K/ubiquitin, and E2-25K/UBB(+1) complex. The structures revealed that ubiquitin or UBB(+1) is bound to E2-25K via the enzyme MGF motif and residues in α9 of the enzyme. Polyubiquitylation assays together with analyses of various E2-25K mutants showed that disrupting UBB(+1) binding markedly diminishes synthesis of neurotoxic UBB(+1)-anchored polyubiquitin. These results suggest that the interaction between E2-25K and UBB(+1) is critical for the synthesis and accumulation of UBB(+1)-anchored polyubiquitin, which results in proteasomal inhibition and neuronal cell death.
authors.affiliation: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea.
authors.forename: Sunggeon
authors.initials: S
authors.lastname: Ko
authors.forename: Gil Bu
authors.initials: GB
authors.lastname: Kang
authors.forename: Sung Min
authors.initials: SM
authors.lastname: Song
authors.forename: Jung-Gyu
authors.initials: JG
authors.lastname: Lee
authors.forename: Dong Yeon
authors.initials: DY
authors.lastname: Shin
authors.forename: Ji-Hye
authors.initials: JH
authors.lastname: Yun
authors.forename: Yi
authors.initials: Y
authors.lastname: Sheng
authors.forename: Chaejoon
authors.initials: C
authors.lastname: Cheong
authors.forename: Young Ho
authors.initials: YH
authors.lastname: Jeon
authors.forename: Yong-Keun
authors.initials: YK
authors.lastname: Jung
authors.forename: Cheryl H
authors.initials: CH
authors.lastname: Arrowsmith
authors.forename: George V
authors.initials: GV
authors.lastname: Avvakumov
authors.forename: Sirano
authors.initials: S
authors.lastname: Dhe-Paganon
authors.forename: Yung Joon
authors.initials: YJ
authors.lastname: Yoo
authors.forename: Soo Hyun
authors.initials: SH
authors.lastname: Eom
authors.forename: Weontae
authors.initials: W
authors.lastname: Lee
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival; D018360:Crystallography, X-Ray; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D006860:Hydrogen Bonding; D009682:Magnetic Resonance Spectroscopy; D008856:Microscopy, Fluorescence; D008958:Models, Molecular; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000737:chemistry / Q000378:metabolism*; D009154:Mutation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D025801:Ubiquitin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D044763:Ubiquitin-Conjugating Enzymes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D046912:Multiprotein Complexes; D011993:Recombinant Fusion Proteins; C479419:UBB protein, human; D025801:Ubiquitin; D049452:Green Fluorescent Proteins; C100879:UBE2K protein, human; D044763:Ubiquitin-Conjugating Enzymes; D046988:Proteasome Endopeptidase Complex
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