2N90

TrkA transmembrane domain NMR structure in DPC micelles

2N90 の概要

• エントリーDOI: 10.2210/pdb2n90/pdb
• NMR情報: BMRB: 25872
• 分子名称: High affinity nerve growth factor receptor (1 entity in total)
• 機能のキーワード: neurotrophin receptor, transferase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 8428.18

構造登録者

Nadezhdin, K.,Goncharuk, S.,Arseniev, A. (登録日: 2015-10-29, 公開日: 2016-11-09, 最終更新日: 2024-05-15)

主引用文献

Franco, M.L.,Nadezhdin, K.D.,Goncharuk, S.A.,Mineev, K.S.,Arseniev, A.S.,Vilar, M.
Structural basis of the transmembrane domain dimerization and rotation in the activation mechanism of the TRKA receptor by nerve growth factor.
J.Biol.Chem., 295:275-286, 2020

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 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.

PubMed: 31801826
DOI: 10.1074/jbc.RA119.011312

実験手法

SOLUTION NMR