Substrate-induced modulation of protein-protein interactions within human mitochondrial cytochrome P450-dependent system

E. O. Yablokov, T. A. Sushko, L. A. Kaluzhskiy, A. A. Kavaleuski, Y. V. Mezentsev, P. V. Ershov, A. A. Gilep, S. Ivanov, N. V. Strushkevich

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)

Abstract

Steroidogenesis is strictly regulated at multiple levels, as produced steroid hormones are crucial to maintain physiological functions. Cytochrome P450 enzymes are key players in adrenal steroid hormone biosynthesis and function within short redox-chains in mitochondria and endoplasmic reticulum. However, mechanisms regulating supply of reducing equivalents in the mitochondrial CYP-dependent system are not fully understood. In the present work, we aimed to estimate how the specific steroids, substrates, intermediates and products of multistep reactions modulate protein-protein interactions between adrenodoxin (Adx) and mitochondrial CYP11 s. Using the SPR technology we determined that steroid substrates affect affinity and stability of CYP11s–Adx complexes in an isoform-specific mode. In particular, cholesterol induces a 4-fold increase in the rate of CYP11A1 – Adx complex formation without significant effect on dissociation (koff decreased ∼1.5-fold), overall increasing complex affinity. At the same time steroid substrates decrease the affinity of both CYP11B1 – Adx and CYP11B2 – Adx complexes, predominantly reducing their stability (4–7 fold). This finding reveals differentiation of protein-protein interactions within the mitochondrial pool of CYPs, which have the same electron donor. The regulation of electron supply by the substrates might affect the overall steroid hormones production. Our experimental data provide further insight into protein-protein interactions within CYP-dependent redox chains involved in steroidogenesis.

Original languageEnglish
Article number105793
JournalJournal of Steroid Biochemistry and Molecular Biology
Volume208
DOIs
Publication statusPublished - Apr 2021

Keywords

  • Adrenal steroid biosynthesis
  • Adrenodoxin
  • CYP11A1
  • CYP11B1
  • CYP11B2
  • Cytochrome P450
  • SPR

Fingerprint

Dive into the research topics of 'Substrate-induced modulation of protein-protein interactions within human mitochondrial cytochrome P450-dependent system'. Together they form a unique fingerprint.

Cite this