2N90

TrkA transmembrane domain NMR structure in DPC micelles


Experimental Data Snapshot

  • Method: SOLUTION NMR
  • Conformers Calculated: 100 
  • Conformers Submitted: 10 
  • Selection Criteria: target function 

wwPDB Validation   3D Report Full Report


This is version 1.2 of the entry. See complete history


Literature

Structural basis of the transmembrane domain dimerization and rotation in the activation mechanism of the TRKA receptor by nerve growth factor.

Franco, M.L.Nadezhdin, K.D.Goncharuk, S.A.Mineev, K.S.Arseniev, A.S.Vilar, M.

(2020) J Biol Chem 295: 275-286

  • DOI: https://doi.org/10.1074/jbc.RA119.011312
  • Primary Citation of Related Structures:  
    2N90

  • PubMed Abstract: 

    Tropomyosin-receptor kinases (TRKs) are essential for the development of the nervous system. The molecular mechanism of TRKA activation by its ligand nerve growth factor (NGF) is still unsolved. Recent results indicate that at endogenous levels most of TRKA is in a monomer-dimer equilibrium and that the binding of NGF induces an increase of the dimeric and oligomeric forms of this receptor. An unsolved issue is the role of the TRKA transmembrane domain (TMD) in the dimerization of TRKA and the structural details of the TMD in the active dimer receptor. Here, we found that the TRKA-TMD can form dimers, identified the structural determinants of the dimer interface in the active receptor, and validated this interface through site-directed mutagenesis together with functional and cell differentiation studies. Using in vivo cross-linking, we found that the extracellular juxtamembrane region is reordered after ligand binding. Replacement of some residues in the juxtamembrane region with cysteine resulted in ligand-independent active dimers and revealed the preferred dimer interface. Moreover, insertion of leucine residues into the TMD helix induced a ligand-independent TRKA activation, suggesting that a rotation of the TMD dimers underlies NGF-induced TRKA activation. Altogether, our findings indicate that the transmembrane and juxtamembrane regions of TRKA play key roles in its dimerization and activation by NGF.


  • Organizational Affiliation

    Molecular Basis of Neurodegeneration Unit, Institute of Biomedicine of València, Consejo Superior de Investigaciones Científicas, 46010 València, Spain.


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
High affinity nerve growth factor receptor
A, B
39Homo sapiensMutation(s): 0 
Gene Names: NTRK1MTCTRKTRKA
EC: 2.7.10.1
Membrane Entity: Yes 
UniProt & NIH Common Fund Data Resources
Find proteins for P04629 (Homo sapiens)
Explore P04629 
Go to UniProtKB:  P04629
PHAROS:  P04629
GTEx:  ENSG00000198400 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP04629
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: SOLUTION NMR
  • Conformers Calculated: 100 
  • Conformers Submitted: 10 
  • Selection Criteria: target function 

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2016-11-09
    Type: Initial release
  • Version 1.1: 2021-02-10
    Changes: Data collection, Database references
  • Version 1.2: 2023-06-14
    Changes: Database references, Other