7ASY

Transmembrane helix of tumor necrosis factor alpha in trifluorethanol

Summary for 7ASY

• Entry DOI: 10.2210/pdb7asy/pdb
• NMR Information: BMRB: 34567
• Descriptor: Tumor necrosis factor (1 entity in total)
• Functional Keywords: transmembrane domain, helix, trifluorethanol, membrane protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 3701.50

Authors

Guschtschin-Schmidt, N.,Muhle-Goll, C. (deposition date: 2020-10-28, release date: 2020-12-09, Last modification date: 2024-05-15)

Primary citation

Spitz, C.,Schlosser, C.,Guschtschin-Schmidt, N.,Stelzer, W.,Menig, S.,Gotz, A.,Haug-Kroper, M.,Scharnagl, C.,Langosch, D.,Muhle-Goll, C.,Fluhrer, R.
Non-canonical Shedding of TNF alpha by SPPL2a Is Determined by the Conformational Flexibility of Its Transmembrane Helix.
Iscience, 23:101775-101775, 2020

PubMed Abstract: 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.

PubMed: 33294784
DOI: 10.1016/j.isci.2020.101775

Experimental method

SOLUTION NMR