Both the sequence and length of the C terminus of PEN-2 are critical for intermolecular interactions and function of presenilin complexes.
Presenilin 1 or presenilin 2, nicastrin, APH-1, and PEN-2 form high molecular weight complexes that play a pivotal role in the cleavage of various Type I transmembrane proteins, including the beta-amyloid precursor protein. The specific function of PEN-2 is unclear. To explore its function and intermolecular interactions, we conducted deletion and mutagenesis studies on a series of conserved residues at the C terminus of PEN-2. These studies suggest that: 1) both the presence and amino acid sequence of the conserved DYLSF domain at the C terminus of PEN-2 (residues 90-94) is critical for binding PEN-2 to other components in the presenilin complex and 2) the overall length of the exposed C terminus is critical for functional gamma-secretase activity.
Centre for Research in Neurodegenerative Diseases, University of Toronto, West Toronto, Ontario M5S 3H2, Canada.
Hiroshi
H
Hasegawa
Nobuo
N
Sanjo
Fusheng
F
Chen
Yong-Jun
YJ
Gu
Cortney
C
Shier
Agnes
A
Petit
Toshitaka
T
Kawarai
Taiichi
T
Katayama
Stephen D
SD
Schmidt
Paul M
PM
Mathews
Gerold
G
Schmitt-Ulms
Paul E
PE
Fraser
Peter
P
St George-Hyslop
D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000737:chemistry; D000818:Animals; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D002499:Centrifugation, Density Gradient; D003513:Cycloheximide / Q000494:pharmacology; D018076:DNA, Complementary / Q000378:metabolism; D017353:Gene Deletion; D015723:Gene Library; D006801:Humans; D047468:Immunoprecipitation; D008565:Membrane Proteins / Q000737:chemistry* / Q000378:metabolism; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D034622:RNA Interference
D016229:Amyloid beta-Peptides; D018076:DNA, Complementary; D008565:Membrane Proteins; C469349:PSENEN protein, human; D003513:Cycloheximide; D053829:Amyloid Precursor Protein Secretases