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Picture of Gyula Hoffka

Gyula Hoffka

Postdoctoral fellow

Picture of Gyula Hoffka

Phosphorylation of ITIM motifs drives the structural transition of indoleamine 2,3-dioxygenase 1 between enzymatic and non-enzymatic states

Author

  • Gyula Hoffka
  • Lilla Hornyák
  • Lóránt Székvölgyi
  • Márton Miskei

Summary, in English

Indoleamine 2,3-dioxygenase 1 (IDO1) is the rate-limiting enzyme in tryptophan metabolism that plays a central role in immune regulation across a range of diseases, including cancer. Beyond its enzymatic role, IDO1 has a non-enzymatic function that remains poorly understood. This study explores how phosphorylation of immunoreceptor tyrosine-based inhibitory motifs (ITIMs) modulates IDO1's structural dynamics and functional states. Using molecular dynamics simulations and structural analysis, we show that phosphorylation acts as a molecular switch, inducing conformational changes that regulate heme-binding, remodel specific loop regions, and govern protein–protein interactions with SHP1, SHP2, and SOCS3. Notably, Tyr249 phosphorylation inhibits enzymatic activity by compacting the heme-binding pocket, creating steric hindrance that prevents cofactor binding. In contrast, Tyr111 phosphorylation enhances interactions with SHP1 or SHP2 proteins by embedding their C-terminal regions into the heme-binding pocket, also obstructing heme binding. Furthermore, Tyr249 phosphorylation promotes SOCS3 binding through the formation of a unique loop structure near the phosphorylation site. These findings provide a detailed mechanistic framework for understanding how ITIM phosphorylation orchestrates IDO1's functional transitions, effectively balancing its enzymatic and non-enzymatic functions.

Department/s

  • Computational Chemistry

Publishing year

2025-06

Language

English

Publication/Series

Protein Science

Volume

34

Issue

6

Document type

Journal article

Publisher

The Protein Society

Topic

  • Cell and Molecular Biology
  • Theoretical Chemistry (including Computational Chemistry)

Keywords

  • heme binding
  • IDO1
  • immune modulation
  • immunoreceptor tyrosine-based inhibitory motifs (ITIMs)
  • indoleamine 2,3-dioxygenase 1
  • molecular dynamics
  • SHP1
  • SHP2
  • SOCS3

Status

Published

ISBN/ISSN/Other

  • ISSN: 0961-8368