Kinase Subfamily MNK

Kinase Classification: Group CAMK: Family MAPKAPK: Subfamily MNK

Mnk kinases are activated by MAPK (MNK: MAPK iNteracting Kinases, aka MKNK), and control protein translation by phosphorylation of the translation initiation factor eIF4E.

Mnk kinases bind eIF4G allowing them to phosphorylate eIF4E, and play a role in diet-responsive cell growth and metabolism. They are activated by Erk and p38 MAPKs. Phosphorylation of Mnk1 by Pak2 reduces binding to eIF4G and phosphorylation of eIF4E [1].

All MNK kinases have a unique substitution of the DFG motif to DFD. In a crystal structure, this altered motif is found to block ATP binding, in a "DFG-out" manner [2]. Replacement of DFD with DFG creates a structure that has both DFG-in and DFG-out conformations, though no clear functional difference. All MNK kinases also share a cysteine-rich 10-AA insert in the kinase domain between the F and G helices ("I3 box") relative to other MAPKAPK. The sequence in and around this insert has four MNK-conserved cysteines (CGSDCGWDRGEACPACQ in human MNK2). which form a zinc-co-ordination site as seen in the structure. They are thought not to affect catalytic ability, though they may change conformation for binding to interacting proteins.

References

1. Orton KC, Ling J, Waskiewicz AJ, Cooper JA, Merrick WC, Korneeva NL, Rhoads RE, Sonenberg N, and Traugh JA. Phosphorylation of Mnk1 by caspase-activated Pak2/gamma-PAK inhibits phosphorylation and interaction of eIF4G with Mnk. J Biol Chem. 2004 Sep 10;279(37):38649-57. DOI:10.1074/jbc.M407337200 |
2. Jauch R, Jäkel S, Netter C, Schreiter K, Aicher B, Jäckle H, and Wahl MC. Crystal structures of the Mnk2 kinase domain reveal an inhibitory conformation and a zinc binding site. Structure. 2005 Oct;13(10):1559-68. DOI:10.1016/j.str.2005.07.013 |