A mechanism of global shape-dependent recognition and phosphorylation of filamin by protein kinase A.
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Ithychanda SS, Fang X, Mohan ML, Zhu L, Tirupula KC, Naga Prasad SV, Wang YX, Karnik SS, Qin J
A mechanism of global shape-dependent recognition and phosphorylation of filamin by protein kinase A.
J Biol Chem. 2015 Mar 27;290(13):8527-38. doi: 10.1074/jbc.M114.633446. Epub 2015 Feb 9.
- PubMed ID
- 25666618 [ View in PubMed]
- Abstract
Protein phosphorylation mediates essentially all aspects of cellular life. In humans, this is achieved by approximately 500 kinases, each recognizing a specific consensus motif (CM) in the substrates. The majority of CMs are surface-exposed and are thought to be accessible to kinases for phosphorylation. Here we investigated the archetypical protein kinase A (PKA)-mediated phosphorylation of filamin, a major cytoskeletal protein that can adopt an autoinhibited conformation. Surprisingly, autoinhibited filamin is refractory to phosphorylation by PKA on a known Ser(2152) site despite its CM being exposed and the corresponding isolated peptide being readily phosphorylated. Structural analysis revealed that although the CM fits into the PKA active site its surrounding regions sterically clash with the kinase. However, upon ligand binding, filamin undergoes a conformational adjustment, allowing rapid phosphorylation on Ser(2152). These data uncover a novel ligand-induced conformational switch to trigger filamin phosphorylation. They further suggest a substrate shape-dependent filtering mechanism that channels specific exposed CM/kinase recognition in diverse signaling responses.