Phosphorylation of ITIM motifs drives the structural transition of indoleamine 2,3-dioxygenase 1 between enzymatic and non-enzymatic states
(2025) In Protein Science 34(6).- Abstract
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... (More)
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.
(Less)
- author
- Hoffka, Gyula LU ; Hornyák, Lilla ; Székvölgyi, Lóránt and Miskei, Márton
- organization
- publishing date
- 2025-06
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- heme binding, IDO1, immune modulation, immunoreceptor tyrosine-based inhibitory motifs (ITIMs), indoleamine 2,3-dioxygenase 1, molecular dynamics, SHP1, SHP2, SOCS3
- in
- Protein Science
- volume
- 34
- issue
- 6
- article number
- e70152
- publisher
- The Protein Society
- external identifiers
-
- scopus:105005283333
- pmid:40371730
- ISSN
- 0961-8368
- DOI
- 10.1002/pro.70152
- language
- English
- LU publication?
- yes
- id
- 3ced10a5-3889-4dbb-a8d0-e7a0eb0b1b65
- date added to LUP
- 2025-07-30 11:24:44
- date last changed
- 2025-07-31 03:00:03
@article{3ced10a5-3889-4dbb-a8d0-e7a0eb0b1b65,
abstract = {{<p>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.</p>}},
author = {{Hoffka, Gyula and Hornyák, Lilla and Székvölgyi, Lóránt and Miskei, Márton}},
issn = {{0961-8368}},
keywords = {{heme binding; IDO1; immune modulation; immunoreceptor tyrosine-based inhibitory motifs (ITIMs); indoleamine 2,3-dioxygenase 1; molecular dynamics; SHP1; SHP2; SOCS3}},
language = {{eng}},
number = {{6}},
publisher = {{The Protein Society}},
series = {{Protein Science}},
title = {{Phosphorylation of ITIM motifs drives the structural transition of indoleamine 2,3-dioxygenase 1 between enzymatic and non-enzymatic states}},
url = {{http://dx.doi.org/10.1002/pro.70152}},
doi = {{10.1002/pro.70152}},
volume = {{34}},
year = {{2025}},
}