Abstract:
:Phosphorylation of membrane proteins is a central regulatory and signaling mechanism across cell compartments. However, the recognition process and phosphorylation mechanism of membrane-bound substrates by kinases are virtually unknown. cAMP-dependent protein kinase A (PKA) is a ubiquitous enzyme that phosphorylates several soluble and membrane-bound substrates. In cardiomyocytes, PKA targets phospholamban (PLN), a membrane protein that inhibits the sarcoplasmic reticulum Ca(2+)-ATPase (SERCA). In the unphosphorylated state, PLN binds SERCA, reducing the calcium uptake and generating muscle contraction. PKA phosphorylation of PLN at S16 in the cytoplasmic helix relieves SERCA inhibition, initiating muscle relaxation. Using steady-state kinetic assays, NMR spectroscopy, and molecular modeling, we show that PKA recognizes and phosphorylates the excited, membrane-detached R-state of PLN. By promoting PLN from a ground state to an excited state, we obtained a linear relationship between rate of phosphorylation and population of the excited state of PLN. The conformational equilibrium of PLN is crucial to regulate the extent of PLN phosphorylation and SERCA inhibition.
journal_name
J Mol Bioljournal_title
Journal of molecular biologyauthors
Masterson LR,Yu T,Shi L,Wang Y,Gustavsson M,Mueller MM,Veglia Gdoi
10.1016/j.jmb.2011.06.041subject
Has Abstractpub_date
2011-09-16 00:00:00pages
155-64issue
2eissn
0022-2836issn
1089-8638pii
S0022-2836(11)00716-9journal_volume
412pub_type
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