Non-canonical Shedding of TNFα by SPPL2a Is Determined by the Conformational Flexibility of Its Transmembrane Helix.
Biochemistry
Biophysics
Structural Biology
Journal
iScience
ISSN: 2589-0042
Titre abrégé: iScience
Pays: United States
ID NLM: 101724038
Informations de publication
Date de publication:
18 Dec 2020
18 Dec 2020
Historique:
received:
17
08
2020
revised:
21
10
2020
accepted:
03
11
2020
entrez:
9
12
2020
pubmed:
10
12
2020
medline:
10
12
2020
Statut:
epublish
Résumé
Ectodomain (EC) shedding defines the proteolytic removal of a membrane protein EC and acts as an important molecular switch in signaling and other cellular processes. Using tumor necrosis factor (TNF)α as a model substrate, we identify a non-canonical shedding activity of SPPL2a, an intramembrane cleaving aspartyl protease of the GxGD type. Proline insertions in the TNFα transmembrane (TM) helix strongly increased SPPL2a non-canonical shedding, while leucine mutations decreased this cleavage. Using biophysical and structural analysis, as well as molecular dynamic simulations, we identified a flexible region in the center of the TNFα wildtype TM domain, which plays an important role in the processing of TNFα by SPPL2a. This study combines molecular biology, biochemistry, and biophysics to provide insights into the dynamic architecture of a substrate's TM helix and its impact on non-canonical shedding. Thus, these data will provide the basis to identify further physiological substrates of non-canonical shedding in the future.
Identifiants
pubmed: 33294784
doi: 10.1016/j.isci.2020.101775
pii: S2589-0042(20)30972-X
pmc: PMC7689174
doi:
Types de publication
Journal Article
Langues
eng
Pagination
101775Informations de copyright
© 2020 The Authors.
Déclaration de conflit d'intérêts
The authors declare no competing interests.
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