7AT7

Transmembrane helix of tumor necrosis factor alpha in trifluorethanol, S34P mutant


Experimental Data Snapshot

  • Method: SOLUTION NMR
  • Conformers Calculated: 200 
  • Conformers Submitted: 20 
  • Selection Criteria: structures with the lowest energy 

wwPDB Validation   3D Report Full Report


This is version 1.2 of the entry. See complete history


Literature

Non-canonical Shedding of TNF alpha by SPPL2a Is Determined by the Conformational Flexibility of Its Transmembrane Helix.

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.

(2020) iScience 23: 101775-101775

  • DOI: https://doi.org/10.1016/j.isci.2020.101775
  • Primary Citation of Related Structures:  
    7ASY, 7AT7, 7ATB

  • 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.


  • Organizational Affiliation

    Biochemistry and Molecular Biology, Institute of Theoretical Medicine, Medical Faculty, University of Augsburg, Universitätsstrasse 2, 86159 Augsburg, Germany.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Tumor necrosis factor33Homo sapiensMutation(s): 1 
Membrane Entity: Yes 
UniProt & NIH Common Fund Data Resources
Find proteins for P01375 (Homo sapiens)
Explore P01375 
Go to UniProtKB:  P01375
PHAROS:  P01375
GTEx:  ENSG00000232810 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP01375
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: SOLUTION NMR
  • Conformers Calculated: 200 
  • Conformers Submitted: 20 
  • Selection Criteria: structures with the lowest energy 

Structure Validation

View Full Validation Report



Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
German Research Foundation (DFG)GermanyMU1606/6-2

Revision History  (Full details and data files)

  • Version 1.0: 2020-12-09
    Type: Initial release
  • Version 1.1: 2020-12-23
    Changes: Database references
  • Version 1.2: 2024-05-15
    Changes: Data collection, Database references