Autoactivation Is the Key

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Science  20 Jun 2008:
Vol. 320, Issue 5883, pp. 1564
DOI: 10.1126/science.320.5883.1564b

Protein tyrosine kinases (PTKs) regulate cellular activities by transferring phosphate groups from ATP to other proteins. PTKs must first be activated by autophosphorylation of their own specific tyrosine residues. The structural basis for eukaryotic PTK activation involves displacement of an amino acid loop, which initially blocks access to the active site but shifts out of the way upon autophosphorylation. Much less is known about prokaryotic PTKs, which do not have significant sequence homology to eukaryotic PTKs.

Lee et al. have determined the crystal structure of a prokaryotic PTK domain from the Escherichia coli tyrosine kinase Etk, alone and with ADP bound. The side chain of tyrosine 574 (Y574), which must be autophosphorylated in order to activate Etk, is positioned facing ADP in the active site and blocks access by peptide substrates. Although Y574 is not part of a flexible loop, a phosphorylated Y574 side chain could rotate away from the active site into an alternate conformation that would be stabilized by a salt bridge to a nearby arginine and multiple hydrogen bonds to surrounding amino acids. The Etk structure therefore suggests a new mechanism of activation of PTKs, in which phosphorylation-triggered displacement of only a single amino acid side chain suffices to unlock the door to the active site. — NM*

EMBO J. 27, 10.1038/emboj.2008.97 (2008).

  • * Nilah Monnier is a summer intern in Science's editorial department.

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