Abstract
Phosphorylation is one of the major mechanisms for posttranscriptional modification of proteins. The addition of a compact, negatively charged moiety to a protein can significantly change its function and localization by affecting its structure and interaction network. We have used all-atom Molecular Dynamics simulations to investigate the structural consequences of phosphorylating the Na(+)/K(+)-ATPase (NKA) residue Ser(936), which is the best characterized phosphorylation site in NKA, targeted in vivo by protein kinase A (PKA). The Molecular Dynamics simulations suggest that Ser(936) phosphorylation opens a C-terminal hydrated pathway leading to Asp(926), a transmembrane residue proposed to form part of the third sodium ion-binding site. Simulations of a S936E mutant form, for which only subtle effects are observed when expressed in Xenopus oocytes and studied with electrophysiology, does not mimic the effects of Ser(936) phosphorylation. The results establish a structural association of Ser(936) with the C terminus of NKA and indicate that phosphorylation of Ser(936) can modulate pumping activity by changing the accessibility to the ion-binding site.
| Original language | English |
|---|---|
| Journal | Journal of Biological Chemistry |
| Volume | 287 |
| Issue | 19 |
| Pages (from-to) | 15959-15965 |
| Number of pages | 7 |
| ISSN | 0021-9258 |
| DOIs | |
| Publication status | Published - 4 May 2012 |
Keywords
- Animals
- Binding Sites
- Cyclic AMP-Dependent Protein Kinases
- Female
- Humans
- Hydrogen Bonding
- Models, Molecular
- Molecular Dynamics Simulation
- Mutation
- Phosphorylation
- Protein Structure, Secondary
- Protein Structure, Tertiary
- Protein Subunits
- Sodium
- Sodium-Potassium-Exchanging ATPase
- Swine
- Water
- Xenopus laevis