The membrane topology of RTN3 and its effect on binding of RTN3 to BACE1.
Reticulon 3 (RTN3) has recently been shown to modulate Alzheimer BACE1 activity and to play a role in the formation of dystrophic neurites present in Alzheimer brains. Despite the functional importance of this protein in Alzheimer disease pathogenesis, the functional correlation to the structural domain of RTN3 remained unclear. RTN3 has two long transmembrane domains, but its membrane topology was not known. We report here that the first transmembrane domain dictates membrane integration and its membrane topology. RTN3 adopts a omega-shape structure with two ends facing the cytosolic side. Subtle changes in RTN3 membrane topology can disrupt its binding to BACE1 and its inhibitory effects on BACE1 activity. Thus, the determination of RTN3 membrane topology may provide an important structural basis for our understanding of its cellular functions.
He
Wanxia
W
Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
Shi
Qi
Q
Hu
Xiangyou
X
Yan
Riqiang
R
D000544:Alzheimer Disease / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics*; D016282:Aspartic Acid Endopeptidases / Q000235:genetics*; D001921:Brain / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics*; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism*; D019286:Endopeptidase K / Q000737:chemistry; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D008861:Microsomes / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D009419:Nerve Tissue Proteins / Q000235:genetics*; D011485:Protein Binding; D014176:Protein Biosynthesis; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D014158:Transcription, Genetic
D002352:Carrier Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C476198:RTN3 protein, human; D053829:Amyloid Precursor Protein Secretases; D019286:Endopeptidase K; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human