Navigating the ERK1/2 MAPK Cascade

Biomolecules, Journal Year: 2023, Volume and Issue: 13(10), P. 1555 - 1555

Published: Oct. 20, 2023

The RAS-ERK pathway is a fundamental signaling cascade crucial for many biological processes including proliferation, cell cycle control, growth, and survival; common across all types. Notably, ERK1/2 are implicated in specific context-dependent manner as stem cells pancreatic β-cells. Alterations the different components of this result dysregulation effector kinases which communicate with hundreds substrates. Aberrant activation contributes to range disorders, cancer. This review provides an overview structure, activation, regulation, mutational frequency tiers cascade; particular focus on ERK1/2. We highlight importance scaffold proteins that contribute kinase localization coordinate interaction dynamics substrates, activators, inhibitors. Additionally, we explore innovative therapeutic approaches emphasizing promising avenues field.

Language: Английский

---

Allo-targeting of the kinase domain: Insights from in silico studies and comparison with experiments

Current Opinion in Structural Biology, Journal Year: 2024, Volume and Issue: 84, P. 102770 - 102770

Published: Jan. 11, 2024

Language: Английский

---

ERK Allosteric Activation: The Importance of Two Ordered Phosphorylation Events

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: March 2, 2025

Abstract ERK, a coveted proliferation drug target, is pivotal kinase in the Ras/ERK signaling cascade. Despite this, crucial questions about its activation have not been fully explored on foundational, conformational level. Such include (i) Why ERK’s demands dual phosphorylation ; (ii) What role of each site loop and (iii) Exactly how (ordered) steps affect ensembles , their propensities restriction to narrower range favoring catalytic action . Here we used explicit molecular dynamics simulations study stability changes different stages along process. The initial monophosphorylation event elongates enable successive phosphorylations, which reintroduce stability/compactness through newly formed salt bridges. interactions by are site-dependent, with threonine’s presenting stronger electrostatic compared tyrosine’s. Dual phosphorylated ERKs revealed compact structure allows HRD motif stabilize ATP. We further observe that hinge homodimerization binding responded tri-state code based solely degree (unphosphorylated, monophosphorylated, phosphorylated) loop, confirming can allosterically influence distant regions. Last, our findings indicate threonine as second step necessary for ERK become effectively activated depends order. Collectively, offer allosteric explain why order crucial.

Language: Английский

---

ERK Allosteric Activation: The Importance of Two Ordered Phosphorylation Events

Journal of Molecular Biology, Journal Year: 2025, Volume and Issue: unknown, P. 169130 - 169130

Published: April 1, 2025

Language: Английский

---

Conformation selection by ATP-competitive inhibitors and allosteric communication in ERK2

eLife, Journal Year: 2023, Volume and Issue: 12

Published: Sept. 28, 2023

Activation of the extracellular signal-regulated kinase-2 (ERK2) by phosphorylation has been shown to involve changes in protein dynamics, as determined hydrogen-deuterium exchange mass spectrometry (HDX-MS) and NMR relaxation dispersion measurements. These can be described a global between two conformational states active kinase, named ‘L’ ‘R,’ where R is associated with catalytically productive ATP-binding mode. An ATP-competitive ERK1/2 inhibitor, Vertex-11e, properties conformation selection for R-state, revealing movements activation loop that are allosterically coupled kinase site. However, features inhibitors important R-state unknown. Here, we survey panel ERK using HDX-MS identify 14 new molecules selection. They reveal effects propagated distal regions P +1 helix αF segments surrounding loop, well αL16. Crystal structures inhibitor complexes ERK2 systematic shifts Gly αC, mediated Tyr-Tyr ring stacking interaction conserved Lys-Glu salt bridge. The findings suggest model involving small N-lobe promote compactness within site alter mobility loop. Such might exploited modulate docking interface used substrates effectors.

Language: Английский

---

Probing conformational dynamics to understand kinase inhibition

eLife, Journal Year: 2023, Volume and Issue: 12

Published: Oct. 18, 2023

Why do some inhibitors select the on-state in ERK2, a kinase that is involved many signaling pathways cells, whereas others bind to more than one conformation?

Language: Английский

---

Special Issue: MAPK Signaling Cascades in Human Health and Diseases

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(20), P. 11226 - 11226

Published: Oct. 18, 2024

In order to survive and fulfil their functions, cells of any organism need be able respond a large number extracellular factors, also termed stimuli [...]

Language: Английский

---