Journal Article

DZNE-2024-00122

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Cleavage efficiency of the intramembrane protease γ-secretase is reduced by the palmitoylation of a substrate's transmembrane domain.

Aßfalg, M. (First author)DZNE* ; Güner, G.DZNE* ; Müller, S. A.DZNE* ; Breimann, S.DZNE* ; Langosch, D. ; Muhle-Goll, C. ; Frishman, D. ; Steiner, H.DZNE* ; Lichtenthaler, S. F. (Last author)DZNE*

2024
Wiley Hoboken, NJ

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Please use a persistent id in citations: doi:10.1096/fj.202302152R

Abstract: The intramembrane protease γ-secretase has broad physiological functions, but also contributes to Notch-dependent tumors and Alzheimer's disease. While γ-secretase cleaves numerous membrane proteins, only few nonsubstrates are known. Thus, a fundamental open question is how γ-secretase distinguishes substrates from nonsubstrates and whether sequence-based features or post-translational modifications of membrane proteins contribute to substrate recognition. Using mass spectrometry-based proteomics, we identified several type I membrane proteins with short ectodomains that were inefficiently or not cleaved by γ-secretase, including 'pituitary tumor-transforming gene 1-interacting protein' (PTTG1IP). To analyze the mechanism preventing cleavage of these putative nonsubstrates, we used the validated substrate FN14 as a backbone and replaced its transmembrane domain (TMD), where γ-cleavage occurs, with the one of nonsubstrates. Surprisingly, some nonsubstrate TMDs were efficiently cleaved in the FN14 backbone, demonstrating that a cleavable TMD is necessary, but not sufficient for cleavage by γ-secretase. Cleavage efficiencies varied by up to 200-fold. Other TMDs, including that of PTTG1IP, were still barely cleaved within the FN14 backbone. Pharmacological and mutational experiments revealed that the PTTG1IP TMD is palmitoylated, which prevented cleavage by γ-secretase. We conclude that the TMD sequence of a membrane protein and its palmitoylation can be key factors determining substrate recognition and cleavage efficiency by γ-secretase.

Keyword(s): Amyloid Precursor Protein Secretases: genetics (MeSH) ; Amyloid Precursor Protein Secretases: metabolism (MeSH) ; Lipoylation (MeSH) ; Membrane Proteins: metabolism (MeSH) ; Protein Domains (MeSH) ; Protein Processing, Post-Translational (MeSH) ; Amyloid beta-Protein Precursor: metabolism (MeSH) ; FXYD3 ; FXYD6 ; LYRIC ; PMEPA1 ; TNR12 ; Tweak receptor ; intramembrane proteolysis ; protease substrate specificity ; Amyloid Precursor Protein Secretases ; Membrane Proteins ; Amyloid beta-Protein Precursor

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Contributing Institute(s):

1. Neuroproteomics (AG Lichtenthaler)
2. Biochemistry of γ-Secretase (AG Steiner)
3. Molecular Neurodegeneration (AG Haass)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)

Appears in the scientific report 2024

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Database coverage:
; ; ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DEAL Wiley ; Ebsco Academic Search ; Essential Science Indicators ; IF < 5 ; JCR ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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Linked articles:

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Dataset Müller, S. A.DZNE* ; Lichtenthaler, S.DZNE*
Dataset: Identification of naturally short gamma-secretase substrates
PRoteomics IDEntifications Database (2024)2024   Fulltext BibTeX | EndNote: XML, Text | RIS

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