Related Experiment Video

Updated: May 14, 2026

Spatial and Temporal Analysis of Active ERK in the C. elegans Germline
08:40

Spatial and Temporal Analysis of Active ERK in the C. elegans Germline

Published on: November 29, 2016

Structural mechanism for the specific assembly and activation of the extracellular signal regulated kinase 5 (ERK5)

Gábor Glatz1, Gergő Gógl1, Anita Alexa1

  • 1Department of Biochemistry, Eötvös Loránd University, Budapest H-1117, Hungary.

The Journal of Biological Chemistry
|February 6, 2013
PubMed

Insights

The Phox and Bem1 (PB1) domain of MKK5 and its linear motif enable specific binding to ERK5, distinct from ERK2. This interaction facilitates the formation of signaling complexes, revealing evolutionary pathways for protein kinase networks.

Area of Science:

  • Molecular Biology
  • Structural Biology
  • Biochemistry

Background:

  • Mitogen-activated protein kinase (MAPK) activation relies on a conserved linear binding motif in MAPK kinases (MKKs).
  • The Phox and Bem1 (PB1) domain of MKK5 is crucial for the activation of extracellular signal-regulated kinase 5 (ERK5).

Purpose of the Study:

  • To elucidate the structural basis of ERK5 activation by MKK5.
  • To compare the protein-protein interaction surfaces of ERK5 and its paralog ERK2.
  • To understand how MKK5's PB1 domain and linear motif contribute to substrate specificity and complex formation.

Main Methods:

  • X-ray crystallography to determine the structure of ERK5 complexed with an MKK5 construct.
  • Biochemical assays to characterize protein-protein interactions and binding specificity.

Main Results:

  • The crystal structure reveals distinct protein-protein interaction surfaces on ERK5 compared to ERK2.
  • The MKK5 PB1 domain and linear motif cooperate for specific ERK5 binding.
  • This interaction facilitates the co-recruitment of upstream activators and downstream substrates into a signaling complex.

Conclusions:

  • ERK5 and ERK2 possess unique interaction surfaces enabling differential binding of activators and substrates, correlating with their distinct physiological roles.
  • The MKK5 PB1 domain is essential for substrate specificity and the assembly of functional signaling complexes.
  • These findings offer insights into the evolution of protein kinase networks, suggesting how paralogs gain new functions through altered protein interactions.

More Related Videos

Subcellular Fractionation for ERK Activation Upon Mitochondrial-derived Peptide Treatment07:55

Subcellular Fractionation for ERK Activation Upon Mitochondrial-derived Peptide Treatment

Published on: September 25, 2017

Deciphering the Structural Effects of Activating EGFR Somatic Mutations with Molecular Dynamics Simulation15:05

Deciphering the Structural Effects of Activating EGFR Somatic Mutations with Molecular Dynamics Simulation

Published on: May 20, 2020

Related Concept Videos

MAPK Signaling Cascades01:07

MAPK Signaling Cascades

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...
Amplifying Signals via Enzymatic Cascade01:22

Amplifying Signals via Enzymatic Cascade

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 the...
Assembly of Signaling Complexes01:30

Assembly of Signaling Complexes

Multiprotein signaling complexes are formed in a dynamic process involving protein-protein interactions at the cytoplasmic domain of transmembrane receptors or enzymatic and non-enzymatic proteins associated with the receptor. These complexes ensure the activation and propagation of intracellular signals that regulate cell functions.
Interaction domains in cell signaling
Interaction domains recognize exposed features of their binding partners containing post-translationally modified sequences,...
Receptor Tyrosine Kinases01:26

Receptor Tyrosine Kinases

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...
Interactions Between Signaling Pathways01:19

Interactions Between Signaling Pathways

Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
Enzyme-linked Receptors01:00

Enzyme-linked Receptors

Enzyme-linked receptors are proteins that act as both receptor and enzyme, activating multiple intracellular signals. This is a large group of receptors that include the receptor tyrosine kinase (RTK) family. Many growth factors and hormones bind to and activate the RTKs.
Neurotrophin (NT) receptors are a family of RTKs, including trkA, trkB, and trkC (tropomyosin-related kinase) receptors. TrkA is specific for nerve growth factor (NGF), neurotrophin-6, and neurotrophin-7. TrkB binds...