SEL-10 interacts with presenilin 1, facilitates its ubiquitination, and alters A-beta peptide production

Jinhe Li; Adele M Pauley; Rick L Myers; Rongqing Shuang; John R Brashler; Riqiang Yan; Allen E Buhl; Cara Ruble; Mark E Gurney

doi:10.1046/j.1471-4159.2002.01105.x

SEL-10 interacts with presenilin 1, facilitates its ubiquitination, and alters A-beta peptide production

J Neurochem. 2002 Sep;82(6):1540-8. doi: 10.1046/j.1471-4159.2002.01105.x.

Authors

Jinhe Li¹, Adele M Pauley, Rick L Myers, Rongqing Shuang, John R Brashler, Riqiang Yan, Allen E Buhl, Cara Ruble, Mark E Gurney

Affiliation

¹ Department of Neurobiology, Computer Aided Drug Design, Pharmacia Corporation, Kalamazoo, Michigan 49001, USA.

PMID: 12354302
DOI: 10.1046/j.1471-4159.2002.01105.x

Abstract

Mutations in the human presenilin genes (PS1 or PS2) have been linked to autosomal dominant, early onset Alzheimer's disease (AD). Presenilins, probably as an essential part of gamma-secretase, modulate gamma-cleavage of the amyloid protein precursor (APP) to the amyloid beta-peptide (Abeta). Mutations in sel-12, a Caenorhabditis elegans presenilin homologue, cause a defect in egg laying that can be suppressed by loss of function mutations in a second gene, SEL-10. SEL-10 protein is a homologue of yeast Cdc4, a member of the SCF (Skp1-Cdc53/CUL1-F-box protein) E2-E3 ubiquitin ligase family. In this study, we show that human SEL-10 interacts with PS1 and enhances PS1 ubiquitination, thus altering cellular levels of unprocessed PS1 and its N- and C-terminal fragments. Co-transfection of sel-10 and APP cDNAs in HEK293 cells leads to an alteration in the metabolism of APP and to an increase in the production of amyloid beta-peptide, the principal component of amyloid plaque in Alzheimer's disease.

MeSH terms

Amino Acid Sequence
Amyloid beta-Peptides / biosynthesis*
Animals
Caenorhabditis elegans
Caenorhabditis elegans Proteins*
Cell Cycle Proteins / genetics*
Cell Cycle Proteins / metabolism*
Cell Cycle Proteins / pharmacology
Cell Line
Cloning, Molecular
DNA, Complementary / genetics
F-Box Proteins*
F-Box-WD Repeat-Containing Protein 7
Helminth Proteins / genetics*
Helminth Proteins / metabolism*
Helminth Proteins / pharmacology
Humans
Kidney / cytology
Kidney / metabolism
Membrane Proteins / metabolism*
Mice
Molecular Sequence Data
Organ Specificity
Presenilin-1
Protein Binding / physiology
Saccharomyces cerevisiae
Saccharomyces cerevisiae Proteins
Sequence Alignment
Sequence Homology, Amino Acid
Transfection
Ubiquitin / metabolism*
Ubiquitin-Protein Ligases*

Substances

Amyloid beta-Peptides
CDC4 protein, S cerevisiae
Caenorhabditis elegans Proteins
Cell Cycle Proteins
DNA, Complementary
F-Box Proteins
F-Box-WD Repeat-Containing Protein 7
FBXW7 protein, human
Fbxw7 protein, mouse
Helminth Proteins
Membrane Proteins
PSEN1 protein, human
Presenilin-1
SEL-10 protein, C elegans
Saccharomyces cerevisiae Proteins
Ubiquitin
Ubiquitin-Protein Ligases