Membrane Anchoring of Hck Kinase via the Intrinsically Disordered SH4-U and Length Scale Associated with Subcellular Localization.
Hck
Src family kinase
intrinsically disordered protein
membrane
Journal
Journal of molecular biology
ISSN: 1089-8638
Titre abrégé: J Mol Biol
Pays: Netherlands
ID NLM: 2985088R
Informations de publication
Date de publication:
17 04 2020
17 04 2020
Historique:
received:
18
09
2019
revised:
22
11
2019
accepted:
25
11
2019
pubmed:
27
12
2019
medline:
31
10
2020
entrez:
27
12
2019
Statut:
ppublish
Résumé
Src family kinases (SFKs) are a group of nonreceptor tyrosine kinases that are characterized by their involvement in critical signal transduction pathways. SFKs are often found attached to membranes, but little is known about the conformation of the protein in this environment. Here, solution nuclear magnetic resonance (NMR), neutron reflectometry (NR), and molecular dynamics (MD) simulations were employed to study the membrane interactions of the intrinsically disordered SH4 and Unique domains of the Src family kinase Hck. Through development of a procedure to combine the information from the different techniques, we were able produce a first-of-its-kind atomically detailed structural ensemble of a membrane-bound intrinsically disordered protein. Evaluation of the model demonstrated its consistency with previous work and provided insight into how SFK Unique domains act to differentiate the family members from one another. Fortuitously, the position of the ensemble on the membrane allowed the model to be combined with configurations of the multidomain Hck kinase previously determined from small-angle solution X-ray scattering to produce full-length models of membrane-anchored Hck. The resulting models allowed us to estimate that the kinase active site is positioned about 65 ± 35 Å away from the membrane surface, offering the first estimations of the length scale associated with the concept of SFK subcellular localization.
Identifiants
pubmed: 31877324
pii: S0022-2836(19)30721-1
doi: 10.1016/j.jmb.2019.11.024
pmc: PMC7301414
mid: NIHMS1547455
pii:
doi:
Substances chimiques
HCK protein, human
EC 2.7.10.2
Proto-Oncogene Proteins c-hck
EC 2.7.10.2
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
2985-2997Subventions
Organisme : NCI NIH HHS
ID : R01 CA093577
Pays : United States
Organisme : NIH HHS
ID : S10 OD018495
Pays : United States
Informations de copyright
Copyright © 2019 Elsevier Ltd. All rights reserved.
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