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

Publication ,  Journal Article
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 in: Cell Rep
September 27, 2012

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.

Duke Scholars

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Published In

Cell Rep

DOI

EISSN

2211-1247

Publication Date

September 27, 2012

Volume

2

Issue

3

Start / End Page

518 / 525

Location

United States

Related Subject Headings

  • Serine
  • Protein Serine-Threonine Kinases
  • Phosphorylation
  • Escherichia coli Proteins
  • Escherichia coli
  • Drug Resistance, Multiple, Bacterial
  • Amino Acid Motifs
  • Adenosine Triphosphate
  • 31 Biological sciences
  • 1116 Medical Physiology
 

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Schumacher, M. A., Min, J., Link, T. M., Guan, Z., Xu, W., Ahn, Y.-H., … Brennan, R. G. (2012). Role of unusual P loop ejection and autophosphorylation in HipA-mediated persistence and multidrug tolerance. Cell Rep, 2(3), 518–525. https://doi.org/10.1016/j.celrep.2012.08.013
Schumacher, Maria A., JungKi Min, Todd M. Link, Ziqiang Guan, Weijun Xu, Young-Ho Ahn, Erik J. Soderblom, et al. “Role of unusual P loop ejection and autophosphorylation in HipA-mediated persistence and multidrug tolerance.Cell Rep 2, no. 3 (September 27, 2012): 518–25. https://doi.org/10.1016/j.celrep.2012.08.013.
Schumacher MA, Min J, Link TM, Guan Z, Xu W, Ahn Y-H, et al. Role of unusual P loop ejection and autophosphorylation in HipA-mediated persistence and multidrug tolerance. Cell Rep. 2012 Sep 27;2(3):518–25.
Schumacher, Maria A., et al. “Role of unusual P loop ejection and autophosphorylation in HipA-mediated persistence and multidrug tolerance.Cell Rep, vol. 2, no. 3, Sept. 2012, pp. 518–25. Pubmed, doi:10.1016/j.celrep.2012.08.013.
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. Role of unusual P loop ejection and autophosphorylation in HipA-mediated persistence and multidrug tolerance. Cell Rep. 2012 Sep 27;2(3):518–525.
Journal cover image

Published In

Cell Rep

DOI

EISSN

2211-1247

Publication Date

September 27, 2012

Volume

2

Issue

3

Start / End Page

518 / 525

Location

United States

Related Subject Headings

  • Serine
  • Protein Serine-Threonine Kinases
  • Phosphorylation
  • Escherichia coli Proteins
  • Escherichia coli
  • Drug Resistance, Multiple, Bacterial
  • Amino Acid Motifs
  • Adenosine Triphosphate
  • 31 Biological sciences
  • 1116 Medical Physiology