6ens
Structure of mouse wild-type RKIPStructure of mouse wild-type RKIP
Structural highlights
Function[PEBP1_MOUSE] Binds ATP, opioids and phosphatidylethanolamine. Has lower affinity for phosphatidylinositol and phosphatidylcholine. Serine protease inhibitor which inhibits thrombin, neuropsin and chymotrypsin but not trypsin, tissue type plasminogen activator and elastase. Inhibits the kinase activity of RAF1 by inhibiting its activation and by dissociating the RAF1/MEK complex and acting as a competitive inhibitor of MEK phosphorylation (By similarity). HCNP may be involved in the function of the presynaptic cholinergic neurons of the central nervous system. HCNP increases the production of choline acetyltransferase but not acetylcholinesterase. Seems to be mediated by a specific receptor (By similarity). Publication Abstract from PubMedPhosphorylation is a major regulator of protein interactions; however, the mechanisms by which regulation occurs are not well understood. Here we identify a salt-bridge competition or "theft" mechanism that enables a phospho-triggered swap of protein partners by Raf Kinase Inhibitory Protein (RKIP). RKIP transitions from inhibiting Raf-1 to inhibiting G-protein-coupled receptor kinase 2 upon phosphorylation, thereby bridging MAP kinase and G-Protein-Coupled Receptor signaling. NMR and crystallography indicate that a phosphoserine, but not a phosphomimetic, competes for a lysine from a preexisting salt bridge, initiating a partial unfolding event and promoting new protein interactions. Structural elements underlying the theft occurred early in evolution and are found in 10% of homo-oligomers and 30% of hetero-oligomers including Bax, Troponin C, and Early Endosome Antigen 1. In contrast to a direct recognition of phosphorylated residues by binding partners, the salt-bridge theft mechanism represents a facile strategy for promoting or disrupting protein interactions using solvent-accessible residues, and it can provide additional specificity at protein interfaces through local unfolding or conformational change. Conserved salt-bridge competition triggered by phosphorylation regulates the protein interactome.,Skinner JJ, Wang S, Lee J, Ong C, Sommese R, Sivaramakrishnan S, Koelmel W, Hirschbeck M, Schindelin H, Kisker C, Lorenz K, Sosnick TR, Rosner MR Proc Natl Acad Sci U S A. 2017 Dec 5. pii: 1711543114. doi:, 10.1073/pnas.1711543114. PMID:29208709[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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