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PMID: 20178366 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Characterization of an atypical gamma-secretase complex from hematopoietic origin.

Biochemistry ·Vol. 49 ·No. 13 ·2010-04-06 ·Pages 2796-804

Placanica L, Chien JW, Li YM

Abstract

Gamma-secretase is a widely expressed multisubunit enzyme complex which is involved in the pathogenesis of Alzheimer disease and hematopoietic malignancies through its aberrant processing of the amyloid precursor protein (APP) and Notch1, respectively. While gamma-secretase has been extensively studied, there is a dearth of information surrounding the activity, composition, and function of gamma-secretase expressed in distinct cellular populations. Here we show that endogenous gamma-secretase complexes of hematopoietic origin are distinct from epithelial derived gamma-secretase complexes. Hematopoietic gamma-secretase has reduced activity for APP and Notch1 processing compared to epithelial gamma-secretase. Characterization of the active complexes with small molecule affinity probes reveals that hematopoietic gamma-secretase has an atypical subunit composition with significantly altered subunit stoichiometry. Furthermore, we demonstrate that these discrete complexes exhibit cell-line specific substrate selectivity suggesting a possible mechanism of substrate regulation. These data underscore the need for studying endogenous gamma-secretase to fully understand of the biology of gamma-secretase and its complexity as a molecular target for the development of disease therapeutics.

MeSH Terms
Amyloid Precursor Protein Secretases/metabolism Amyloid beta-Protein Precursor/metabolism Blood Cells/enzymology Cell Line Epithelial Cells/enzymology Humans Protein Subunits Receptor, Notch1/metabolism Substrate Specificity
Chemicals
Amyloid beta-Protein Precursor NOTCH1 protein, human Protein Subunits Receptor, Notch1 Amyloid Precursor Protein Secretases
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Placanica Lisa
Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
Chien Jennifer W
Li Yue-Ming
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Article Info
Journal
Biochemistry
Abbr.
Biochemistry
ISSN
1520-4995
DOI
10.1021/bi901388t
Published
2010-04-06
Pages
2796-804
Language
English
Region
United States
NLM ID
0370623
PMCID
PMC2880330
Subset
IM
Grants
NIGMS NIH HHS · T32 GM073546 · United States
NIA NIH HHS · R01 AG026660 · United States
NIA NIH HHS · R01-AG026660 · United States
NIA NIH HHS · R01 AG026660-04 · United States
NIGMS NIH HHS · T32 GM073546-01A1 · United States
External Links
PubMed source DOI: 10.1021/bi901388t PMC Full Text View journal details
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