NDLI: Aph-1 Associates Directly with Full-length and C-terminal Fragments of γ-Secretase Substrates*

Content Provider	PubMed Central
Author	Chen, Allen C. Guo, Lucie Y. Ostaszewski, Beth L. Selkoe, Dennis J. Lavoie, Matthew J.
Abstract	γ-Secretase is a ubiquitous, multiprotein enzyme composed of presenilin, nicastrin, Aph-1, and Pen-2. It mediates the intramembrane proteolysis of many type 1 proteins, plays an essential role in numerous signaling pathways, and helps drive the pathogenesis of Alzheimer disease by excising the hydrophobic, aggregation-prone amyloid β-peptide from the β-amyloid precursor protein. A central unresolved question is how its many substrates bind and enter the γ-secretase complex. Here, we provide evidence that both the β-amyloid precursor protein holoprotein and its C-terminal fragments, the immediate substrates of γ-secretase, can associate with Aph-1 at overexpressed as well as endogenous protein levels. This association was observed using bi-directional co-immunoprecipitation in multiple systems and detergent conditions, and an β-amyloid precursor protein-Aph-1 complex was specifically isolated following in situ cross-linking in living cells. In addition, another endogenous canonical γ-substrate, Jagged, showed association of both its full-length and C-terminal fragment forms with Aph-1. We were also able to demonstrate that this interaction with substrates was conserved across the multiple isoforms of Aph-1 (β, αS, and αL), as they were all able to bind β-amyloid precursor protein with similar affinity. Finally, two highly conserved intramembrane histidines (His-171 and His-197) within Aph-1, which were recently shown to be important for γ-secretase activity, are required for efficient binding of substrates. Taken together, our data suggest a dominant role for Aph-1 in interacting with γ-secretase substrates prior to their processing by the proteolytic complex.
Related Links	http://dx.doi.org/10.1074/jbc.m109.088815
Ending Page	11391
Page Count	14
Starting Page	11378
File Format	PDF
ISSN	00219258
e-ISSN	1083351X
Journal	The Journal of Biological Chemistry
Issue Number	15
Volume Number	285
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	2010-04-09
Access Restriction	Open
Rights Holder	American Society for Biochemistry and Molecular Biology
Subject Keyword	Cell Biology Biochemistry Molecular Biology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

Sl.	Authority	Responsibilities	Communication Details
1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
2	Indian Institute of Technology Kharagpur	Host Institute of the Project: The host institute of the project is responsible for providing infrastructure support and hosting the project	https://www.iitkgp.ac.in
3	National Digital Library of India Office, Indian Institute of Technology Kharagpur	The administrative and infrastructural headquarters of the project	Dr. B. Sutradhar bsutra@ndl.gov.in
4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
5	Website/Portal (Helpdesk)	Queries regarding NDLI and its services	support@ndl.gov.in
6	Contents and Copyright Issues	Queries related to content curation and copyright issues	content@ndl.gov.in
7	National Digital Library of India Club (NDLI Club)	Queries related to NDLI Club formation, support, user awareness program, seminar/symposium, collaboration, social media, promotion, and outreach	clubsupport@ndl.gov.in
8	Digital Preservation Centre (DPC)	Assistance with digitizing and archiving copyright-free printed books	dpc@ndl.gov.in
9	IDR Setup or Support	Queries related to establishment and support of Institutional Digital Repository (IDR) and IDR workshops	idr@ndl.gov.in

Aph-1 Associates Directly with Full-length and C-terminal Fragments of γ-Secretase Substrates

Chemical Cross-linking Provides a Model of the γ-Secretase Complex Subunit Architecture and Evidence for Close Proximity of the C-terminal Fragment of Presenilin with APH-1*

S-Palmitoylation of γ-Secretase Subunits Nicastrin and APH-1* S⃞

Chemical Cross-linking Provides a Model of the γ-Secretase Complex Subunit Architecture and Evidence for Close Proximity of the C-terminal Fragment of Presenilin with APH-1

Identification of Distinct γ-Secretase Complexes with Different APH-1 Variants

Mutation Analysis of the Presenilin 1 N-terminal Domain Reveals a Broad Spectrum of γ-Secretase Activity toward Amyloid Precursor Protein and Other Substrates*

S-Palmitoylation of γ-Secretase Subunits Nicastrin and APH-1

The Transmembrane Domain Region of Nicastrin Mediates Direct Interactions with APH-1 and the γ-Secretase Complex

Glu-333 of Nicastrin Directly Participates in γ-Secretase Activity*

Aph-1 Associates Directly with Full-length and C-terminal Fragments of γ-Secretase Substrates*

Similar Documents

Aph-1 Associates Directly with Full-length and C-terminal Fragments of γ-Secretase Substrates

Chemical Cross-linking Provides a Model of the γ-Secretase Complex Subunit Architecture and Evidence for Close Proximity of the C-terminal Fragment of Presenilin with APH-1*

S-Palmitoylation of γ-Secretase Subunits Nicastrin and APH-1* S⃞

Chemical Cross-linking Provides a Model of the γ-Secretase Complex Subunit Architecture and Evidence for Close Proximity of the C-terminal Fragment of Presenilin with APH-1

Identification of Distinct γ-Secretase Complexes with Different APH-1 Variants

Mutation Analysis of the Presenilin 1 N-terminal Domain Reveals a Broad Spectrum of γ-Secretase Activity toward Amyloid Precursor Protein and Other Substrates*

S-Palmitoylation of γ-Secretase Subunits Nicastrin and APH-1

The Transmembrane Domain Region of Nicastrin Mediates Direct Interactions with APH-1 and the γ-Secretase Complex

Glu-333 of Nicastrin Directly Participates in γ-Secretase Activity*

Aph-1 Associates Directly with Full-length and C-terminal Fragments of γ-Secretase Substrates*