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Structural Insight into the Activation of PknI Kinase from M. tuberculosis via Dimerization of the Extracellular

Qiaoling Yan1, Dunquan Jiang1, Lanfang Qian1

  • 1College of Life Sciences, Nankai University, Tianjin 300071, China.

Structure (London, England : 1993)
|July 18, 2017
PubMed

Insights

Mycobacterium tuberculosis serine/threonine protein kinase I (PknI) sensor domain exists in monomer-dimer equilibrium, crucial for its function. Dimerization activates PknI kinase activity, essential for tuberculosis survival.

Area of Science:

  • Biochemistry
  • Structural Biology
  • Microbiology

Background:

  • Protein kinases are vital for Mycobacterium tuberculosis survival within host cells.
  • Serine/threonine protein kinases (STPKs) are a key family of protein kinases.
  • PknI is a transmembrane STPK implicated in M. tuberculosis pathogenesis.

Purpose of the Study:

  • To determine the high-resolution crystal structures of PknI's sensor and kinase domains.
  • To investigate the monomer-dimer equilibrium of the PknI sensor domain.
  • To elucidate the role of PknI dimerization in its kinase activity and M. tuberculosis growth.

Main Methods:

  • X-ray crystallography was used to determine the structures of the PknI sensor domain (monomer and dimer) and kinase domain.
  • Conformational changes upon sensor domain dimerization were analyzed.
  • Rapamycin-induced dimerization assays were performed on PknI domain fusions.
  • In vivo experiments in an M. bovis model were conducted to assess PknI function.

Main Results:

  • The crystal structures of the PknI sensor domain (PknI_SD) in monomer and dimer forms, and the kinase domain were resolved.
  • PknI_SD is the first identified STPK sensor domain exhibiting monomer-dimer equilibrium.
  • Dimerization of PknI_SD involves a critical arm region and induces conformational changes.
  • Rapamycin-induced dimerization activated the auto-phosphorylation of the PknI kinase domain.
  • In vivo studies indicated PknI functions as a dimer to regulate M. tuberculosis growth.

Conclusions:

  • PknI sensor domain dimerization is a key regulatory mechanism.
  • Dimerization is essential for PknI kinase activation and its role in M. tuberculosis survival.
  • PknI represents a potential therapeutic target for tuberculosis treatment.
Keywords:
Mycobacterium tuberculosisPknISer/Thr protein kinasecrystal structuresensor domain

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