Pitstop‐2 and its novel derivative RVD-127 disrupt global cell dynamics and nuclear pores integrity by direct interaction with small GTPases

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2023
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Liashkovich, Ivan
Stefanello, Sílvio Terra
Vidyadharan, Reshma
Haufe, Günter
Erofeev, Alexander
Gorelkin, Peter V.
Kolmogorov, Vasilii
Mizdal, Caren Rigon
Kouzel, Ian U.
Shahin, Victor
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Bioengineering & Translational Medicine. Wiley. 2023, 8(4), e10425. eISSN 2380-6761. Available under: doi: 10.1002/btm2.10425
Zusammenfassung

Clathrin-mediated endocytosis (CME) is an essential cell physiological process of broad biomedical relevance. Since the recent introduction of Pitstop-2 as a potent CME inhibitor, we and others have reported on substantial clathrin-independent inhibitory effects. Herein, we developed and experimentally validated a novel fluorescent derivative of Pitstop-2, termed RVD-127, to clarify Pitstop-2 diverse effects. Using RVD-127, we were able to trace additional protein targets of Pitstop-2. Besides inhibiting CME, Pitstop-2 and RVD-127 proved to directly and reversibly bind to at least two members of the small GTPase superfamily Ran and Rac1 with particularly high efficacy. Binding locks the GTPases in a guanosine diphosphate (GDP)-like conformation disabling their interaction with their downstream effectors. Consequently, overall cell motility, mechanics and nucleocytoplasmic transport integrity are rapidly disrupted at inhibitor concentrations well below those required to significantly reduce CME. We conclude that Pitstop-2 is a highly potent, reversible inhibitor of small GTPases. The inhibition of these molecular switches of diverse crucial signaling pathways, including nucleocytoplasmic transport and overall cell dynamics and motility, clarifies the diversity of Pitstop-2 activities. Moreover, considering the fundamental importance and broad implications of small GTPases in physiology, pathophysiology and drug development, Pitstop-2 and RVD-127 open up novel avenues.

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Fachgebiet (DDC)
570 Biowissenschaften, Biologie
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atomic force microscopy, cellular physiology, clathrin, nanomedicine, nuclear pores, pharmacology, small GTPases
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ISO 690LIASHKOVICH, Ivan, Sílvio Terra STEFANELLO, Reshma VIDYADHARAN, Günter HAUFE, Alexander EROFEEV, Peter V. GORELKIN, Vasilii KOLMOGOROV, Caren Rigon MIZDAL, Ian U. KOUZEL, Victor SHAHIN, 2023. Pitstop‐2 and its novel derivative RVD-127 disrupt global cell dynamics and nuclear pores integrity by direct interaction with small GTPases. In: Bioengineering & Translational Medicine. Wiley. 2023, 8(4), e10425. eISSN 2380-6761. Available under: doi: 10.1002/btm2.10425
BibTex
@article{Liashkovich2023Pitst-59453,
  year={2023},
  doi={10.1002/btm2.10425},
  title={Pitstop‐2 and its novel derivative RVD-127 disrupt global cell dynamics and nuclear pores integrity by direct interaction with small GTPases},
  number={4},
  volume={8},
  journal={Bioengineering & Translational Medicine},
  author={Liashkovich, Ivan and Stefanello, Sílvio Terra and Vidyadharan, Reshma and Haufe, Günter and Erofeev, Alexander and Gorelkin, Peter V. and Kolmogorov, Vasilii and Mizdal, Caren Rigon and Kouzel, Ian U. and Shahin, Victor},
  note={Article Number: e10425}
}
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