English
 
Help Privacy Policy Disclaimer
  Advanced SearchBrowse

Item

ITEM ACTIONSEXPORT
  14-3-3 binding creates a memory of kinase action by stabilizing the modified state of phospholamban

Menzel, J., Kownatzki-Danger, D., Tokar, S., Ballone, A., Unthan-Fechner, K., Kilisch, M., et al. (2020). 14-3-3 binding creates a memory of kinase action by stabilizing the modified state of phospholamban. Science Signaling, 13(647): eaaz1436. doi:10.1126/scisignal.aaz1436.

Item is

Basic

show hide
Genre: Journal Article

Files

show Files
hide Files
:
3281192.pdf (Publisher version), 2MB
 
File Permalink:
-
Name:
3281192.pdf
Description:
-
Visibility:
Restricted ( Max Planck Society (every institute); )
MIME-Type / Checksum:
application/pdf
Technical Metadata:
Copyright Date:
-
Copyright Info:
-
License:
-

Locators

show

Creators

show
hide
 Creators:
Menzel, J., Author
Kownatzki-Danger, D., Author
Tokar, S., Author
Ballone, A., Author
Unthan-Fechner, K., Author
Kilisch, M., Author
Lenz, C.1, Author              
Urlaub, H.2, Author              
Mori, M., Author
Ottmann, C., Author
Shattock, M. J., Author
Lehnart, S. E., Author
Schwappach, B.3, Author              
Affiliations:
1Research Group of Bioanalytical Mass Spectrometry, MPI for Biophysical Chemistry, Max Planck Society, ou_578613              
2Research Group of Bioanalytical Mass Spectrometry, MPI for biophysical chemistry, Max Planck Society, ou_578613              
3Max Planck Fellow Blanche Schwappach, ou_1548137              

Content

show
hide
Free keywords: -
 Abstract: The cardiac membrane protein phospholamban (PLN) is targeted by protein kinase A (PKA) at Ser16 and by Ca2+/calmodulin-dependent protein kinase II (CaMKII) at Thr17. β-Adrenergic stimulation and PKA-dependent phosphorylation of Ser16 acutely stimulate the sarcoplasmic reticulum calcium pump (SERCA) by relieving its inhibition by PLN. CaMKII-dependent phosphorylation may lead to longer-lasting SERCA stimulation and may sustain maladaptive Ca2+ handling. Here, we demonstrated that phosphorylation at either Ser16 or Thr17 converted PLN into a target for the phosphoadaptor protein 14-3-3 with different affinities. 14-3-3 proteins were localized within nanometers of PLN and endogenous 14-3-3 coimmunoprecipitated with pentameric PLN from cardiac membranes. Molecular dynamics simulations predicted different molecular contacts for peptides phosphorylated at Ser16 or Thr17 with the binding groove of 14-3-3, resulting in varied binding affinities. 14-3-3 binding protected either PLN phosphosite from dephosphorylation. β-Adrenergic stimulation of isolated adult cardiomyocytes resulted in the membrane recruitment of endogenous 14-3-3. The exogenous addition of 14-3-3 to β-adrenergic–stimulated cardiomyocytes led to prolonged SERCA activation, presumably because 14-3-3 protected PLN pentamers from dephosphorylation. Phosphorylation of Ser16 was disrupted by the cardiomyopathy-associated ∆Arg14 mutation, implying that phosphorylation of Thr17 by CaMKII may become crucial for 14-3-3 recruitment to ∆Arg14 PLN. Consistent with PLN acting as a dynamic hub in the control of Ca2+ handling, our results identify 14-3-3 binding to PLN as a contractility-augmenting mechanism.

Details

show
hide
Language(s): eng - English
 Dates: 2020-09-01
 Publication Status: Published online
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1126/scisignal.aaz1436
 Degree: -

Event

show

Legal Case

show

Project information

show

Source 1

show
hide
Title: Science Signaling
Source Genre: Journal
 Creator(s):
Affiliations:
Publ. Info: -
Pages: 16 Volume / Issue: 13 (647) Sequence Number: eaaz1436 Start / End Page: - Identifier: -