Role of unusual P loop ejection and autophosphorylation in HipA-mediated persistence and multidrug tolerance.

Journal Article (Journal Article)

HipA is a bacterial serine/threonine protein kinase that phosphorylates targets, bringing about persistence and multidrug tolerance. Autophosphorylation of residue Ser150 is a critical regulatory mechanism of HipA function. Intriguingly, Ser150 is not located on the activation loop, as are other kinases; instead, it is in the protein core, where it forms part of the ATP-binding "P loop motif." How this buried residue is phosphorylated and regulates kinase activity is unclear. Here, we report multiple structures that reveal the P loop motif's exhibition of a remarkable "in-out" conformational equilibrium, which allows access to Ser150 and its intermolecular autophosphorylation. Phosphorylated Ser150 stabilizes the "out state," which inactivates the kinase by disrupting the ATP-binding pocket. Thus, our data reveal a mechanism of protein kinase regulation that is vital for multidrug tolerance and persistence, as kinase inactivation provides the critical first step in allowing dormant cells to revert to the growth phenotype and to reinfect the host.

Full Text

Duke Authors

Cited Authors

  • Schumacher, MA; Min, J; Link, TM; Guan, Z; Xu, W; Ahn, Y-H; Soderblom, EJ; Kurie, JM; Evdokimov, A; Moseley, MA; Lewis, K; Brennan, RG

Published Date

  • September 27, 2012

Published In

Volume / Issue

  • 2 / 3

Start / End Page

  • 518 - 525

PubMed ID

  • 22999936

Pubmed Central ID

  • PMC4831868

Electronic International Standard Serial Number (EISSN)

  • 2211-1247

Digital Object Identifier (DOI)

  • 10.1016/j.celrep.2012.08.013


  • eng

Conference Location

  • United States