Related Experiment Video
Updated: Feb 28, 2026
07:49
Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
Published on: July 17, 2019
6.6K
Mechanism of MEK1 activation by phosphorylation
Everett Jin1, Levent Sari2, Milo M Lin3
1Lyda Hill Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, Texas; St. Mark's School of Texas, Dallas, Texas.
Biophysical Journal
|February 27, 2026
Summary
Double phosphorylation of MEK1 (MAP kinase kinase 1) progressively unwinds its structure, exposing catalytic residues and enhancing their correlated motion for full enzymatic activation.
Area of Science:
- Biochemistry
- Molecular Biology
- Structural Biology
Background:
- Phosphorylation is a key post-translational modification regulating protein function.
- MEK1 activation requires phosphorylation at S218 and S222, but the mechanism remains unclear.
- Experimental structures of phosphorylated MEK1 are lacking.
Purpose of the Study:
- Investigate the structural and dynamical effects of MEK1 phosphorylation.
- Elucidate the molecular mechanism of MEK1 activation by phosphorylation.
- Understand the cooperative nature of MEK1 phosphorylation.
Main Methods:
- Molecular dynamics simulations were used to model MEK1.
- Simulations analyzed single and double phosphorylation states.
- Conformational entropy and mutual information were calculated.
Main Results:
- Phosphorylation progressively unwinds the helix near phosphorylation sites.
- Phosphate groups rotate to interact with the catalytic site.
- Double phosphorylation exposes all four catalytic residues and induces correlated motion.
Conclusions:
- Phosphorylation-induced partial unfolding increases catalytic residue solvent exposure.
- Dynamical coupling within the active site is critical for MEK1 activity.
- Simulations predict R-spine alignment in double-phosphorylated MEK1, consistent with kinase biology.
Related Concept Videos
01:07MAPK Signaling Cascades
8.8K
Mitogen-activated protein kinase, or MAPK pathway, activates three sequential kinases to regulate cellular responses such as proliferation, differentiation, survival, and apoptosis. The canonical MAPK pathway starts with a mitogen or growth factor binding to an RTK. The activated RTKs stimulate Ras, which recruits Raf or MAP3 Kinase (MAPKKK), the first kinase of the MAPK signaling cascade. Raf further phosphorylates and activates MEK or MAP2 Kinases (MAPKK), which in turn phosphorylates MAP...
8.8K
01:22PI3K/mTOR/AKT Signaling Pathway
5.9K
The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast, mTORC2 consists of a...
5.9K
01:22Amplifying Signals via Enzymatic Cascade
18.7K
When a ligand binds to a cell-surface receptor, the receptor's intracellular domain changes shape, which may either activate its enzyme function or allow its binding to other molecules. The initial signal is amplified by most signal transduction pathways. This means that a single ligand molecule can activate multiple molecules of a downstream target. Proteins that relay a signal are most commonly phosphorylated at one or more sites, activating or inactivating the protein. Kinases catalyze...
18.7K
01:20The JAK-STAT Signaling Pathway
13.4K
Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as SH2...
13.4K
01:26Receptor Tyrosine Kinases
19.9K
Receptor tyrosine kinases or RTKs are membrane-bound receptors that phosphorylate specific tyrosine on protein substrates. RTKs regulate cellular growth, differentiation, survival, and migration. They contain an extracellular ligand binding domain, a transmembrane domain, and a cytosolic tail with intrinsic kinase activity. Several extracellular signaling molecules activate RTKs in one or more ways and relay the signal downstream. Ligands such as platelet-derived growth factor (PDGF) or...
19.9K
02:54Protein Kinases and Phosphatases
15.3K
Proteins undergo chemical modifications that trigger changes in the charge, structure, and conformation of the proteins. Phosphorylation, acetylation, glycosylation, nitrosylation, ubiquitination, lipidation, methylation, and proteolysis are various protein modifications that regulate protein activity. Such modifications are usually enzyme-driven.
Protein kinases
Many proteins in the cell are regulated by phosphorylation, the addition of a phosphate group. A family of enzymes called kinases...
Protein kinases
Many proteins in the cell are regulated by phosphorylation, the addition of a phosphate group. A family of enzymes called kinases...
15.3K