6YHF

Solution NMR Structure of APP TMD


Experimental Data Snapshot

  • Method: SOLUTION NMR
  • Conformers Calculated: 400 
  • Conformers Submitted: 20 
  • Selection Criteria: 20 structures for lowest energy 

wwPDB Validation   3D Report Full Report


This is version 1.2 of the entry. See complete history


Literature

Altered Hinge Conformations in APP Transmembrane Helix Mutants May Affect Enzyme-Substrate Interactions of gamma-Secretase.

Silber, M.Hitzenberger, M.Zacharias, M.Muhle-Goll, C.

(2020) ACS Chem Neurosci 11: 4426-4433

  • DOI: https://doi.org/10.1021/acschemneuro.0c00640
  • Primary Citation of Related Structures:  
    6YHF, 6YHI, 6YHO, 6YHP, 6YHX

  • PubMed Abstract: 

    Cleavage of substrates by γ-secretase is an inherently slow process where substrate-enzyme affinities cannot be broken down into specific sequence requirements in contrast to soluble proteases. Nevertheless, despite its apparent sequence tolerance single point mutations in amyloid precursor protein can severely affect cleavage efficiencies and change product line preferences. We have determined by NMR spectroscopy the structures of the transmembrane domain of amyloid precursor protein in TFE/water and compared it to that of four mutants: two FAD mutants, V44M and I45T, and the two diglycine hinge mutants, G38L and G38P. In accordance with previous publications, the transmembrane domain is composed of two helical segments connected by the diglycine hinge. Mutations alter kink angles and structural flexibility. Furthermore, to our surprise, we observe different, but specific mutual orientations of N- and C-terminal helical segments in the four mutants compared to the wildtype. We speculate that the observed orientations for G38L, G38P, V44M, and I45T lead to unfavorable interactions with γ-secretase exosites during substrate movement to the enzyme's active site in presenilin and/or for the accommodation into the substrate-binding cavity of presenilin.


  • Organizational Affiliation

    Institute for Biological Interfaces 4, Karlsruhe Institute of Technology, P.O. Box 3640, 76021 Karlsruhe, Germany.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Amyloid-beta precursor protein30Homo sapiensMutation(s): 0 
Membrane Entity: Yes 
UniProt & NIH Common Fund Data Resources
Find proteins for P05067 (Homo sapiens)
Explore P05067 
Go to UniProtKB:  P05067
PHAROS:  P05067
GTEx:  ENSG00000142192 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP05067
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: SOLUTION NMR
  • Conformers Calculated: 400 
  • Conformers Submitted: 20 
  • Selection Criteria: 20 structures for lowest energy 

Structure Validation

View Full Validation Report



Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
German Research Foundation (DFG)GermanyFOR2290

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