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Allosteric Activation of Transglutaminase 2 via Inducing an "Open" Conformation for Osteoblast Differentiation

Zhuo Yang1, Xiao-Wen Zhang1, Fang-Fang Zhuo1

  • 1State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|April 23, 2023
PubMed

Insights

Forskolin (FSK) targets transglutaminase 2 (TGM2), promoting osteoblast differentiation and bone formation. This study reveals a new allosteric site on TGM2, offering a potential treatment for osteoporosis.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • Osteoblast dysfunction contributes to skeletal diseases, necessitating new therapeutic targets.
  • Current treatments for osteoporosis require novel pharmacological approaches.

Purpose of the Study:

  • To identify druggable targets for osteoporosis using a chemical genetics approach with forskolin (FSK).
  • To investigate the role of transglutaminase 2 (TGM2) in osteoblast differentiation and its interaction with FSK.

Main Methods:

  • Chemical genetics using FSK as a molecular probe.
  • Identification and characterization of an allosteric site on TGM2.
  • Analysis of TGM2 interactions with mitochondrial proteins.
  • In vivo studies using an ovariectomy mouse model of osteoporosis.

Main Results:

  • FSK significantly induces osteoblast differentiation by targeting TGM2.
  • A novel allosteric site on TGM2 was identified, where FSK binding promotes an open conformation and polyamine incorporation.
  • TGM2 interacts with mitochondrial proteins, enhancing mitochondrial dynamics and ATP production for osteoblast differentiation.
  • FSK treatment ameliorated osteoporosis in an ovariectomy mouse model.

Conclusions:

  • Transglutaminase 2 (TGM2) is a key mediator of FSK-induced osteoblast differentiation.
  • A novel allosteric site on TGM2 presents a promising target for osteoporosis treatment.
  • FSK serves as a valuable chemical tool for studying TGM2 biology and developing bone anabolic agents.
Keywords:
allosteric activationforskolinmitochondriaosteoblast differentiationtransglutaminase 2

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