Every stimulus we encounter influences our bodies at the cellular level. These stimuli can include changes in temperature, water content, pressure, and the surrounding chemical environment. Once a change is detected, a cell needs to respond appropriately to the stimuli. Eukaryotic cells can achieve this through receptors on their cell membrane that detect specific molecules or physical stimuli. This interaction triggers an activation cascade of other effector proteins in the cellular response. One example of these proteins corresponds to Mitogen-activated protein (MAP) kinases that mediate a wide variety of signal transduction pathways.
What are Kinases?
Kinases are enzymes that catalyse the phosphate group transfer from ATP to a specific amino acid on the target protein, a process known as phosphorylation. This post-translational modification can activate or inhibit the target protein. In a cell, different cellular functions can be finely regulated by the addition or removal of phosphate groups. Kinases can be classified depending on the amino acid residue they phosphorylate � primarily serine, threonine or tyrosine. In addition, kinases can be further classified depending on the signalling pathway they participate in. For example, calcium/calmodulin dependent kinases (CaMK) respond to increasing levels of intracellular calcium ions that lead to the activation of other kinases in a signalling cascade.
Mitogen-activated protein (MAP) kinases
MAP kinases (MAPK) are a family of serine/threonine protein kinases that are integral to eukaryotic cellular processes such as cell proliferation, cell differentiation and apoptosis. Typically, MAPK participates in the later stages of a signal transduction pathway. MAPK can phosphorylate a diverse group of substrates located either in the nucleus or cytosol. The ultimate effect is a change in protein function and gene expression to produce an appropriate response to the initial stimulus. MAPK family can be further subdivided into 3 main families: extracellular-signal-regulated kinases (ERKs), Jun amino-terminal kinases (JNKs) and p38 stress-activated protein kinases.
p38 MAP kinase
The p38 MAPK subfamily is primarily responsive to environmental stresses and inflammatory cytokines. When activated, p38 MAPK targets various proteins localised either in the nucleus or cytoplasm, playing a significant role in the inflammatory response. p38 MAPK regulates the production of pro-inflammatory cytokines by modulating cytokines expression via transcription factor modulation. Other roles include cell proliferation and survival.
Like in other kinases, p38 MAPK structure features a conserved core consisting of two lobes: a smaller N-terminal lobe (N-lobe) and a larger C-terminal lobe (C-lobe). The two lobes form a cleft that serves as a docking site for ATP and substrate. These lobes participate in an overall conformational change when the protein is converted from an inactive conformation into a catalytically competent form by phosphorylation of the activation loop. The figure depicts the two lobes that characterise kinases, the different motifs important for catalytic activity, and the conformational change observed in the N-lobe when comparing the active and inactive forms in the protein kinase A (PKA).
Key structural motifs in p38 MAP kinase
HRD motif:
This three-residue long motif (His–Arg–Asp) is responsible for making contacts with the acceptor hydroxyl group in the substrate sequence. For that reason, the aspartic acid in this triad is highly conserved in eukaryotic protein kinases. In the figure, D166 in PAK is observed making a close contact with a cysteine in the substrate peptide.
DFG motif:
Part of the activation loop, this Asp–Phe–Gly motif forms polar contacts with the ATP phosphate groups either directly or indirectly by coordination of magnesium atoms. In the figure, the conserved residue D184 is depicted coordinating two magnesium atoms.
Glycine rich loop:
This loop contains the conserved GXGXXG motif essential for ATP positioning, forming a lid on top of it. In the figure, S53 is observed forming a polar contact with the γ-phosphate.
The role of p38 MAP kinase in cardiomyopathy.
Heart failure, characterised by the heart's reduced capacity to pump blood, is a major cardiovascular disease affecting millions of people worldwide. It has been shown that the p38 MAPK pathway is activated during heart failure, often manifesting as cardiac arrhythmia. Although the exact role of p38 MAPK during heart failure and arrhythmia remains unclear, evidence suggests a detrimental effect of p38 upon activation. Therefore, p38 MAPK has been proposed as a target for drug development. Besides heart failure and cardiac arrhythmia, p38 MAPK activation is also involved in other related heart issues such as cardiac hypertrophy and ischemia reperfusion injury.
About the artwork
Kathryn Elliott (year group 12) a student from Stephen Perse Foundation, created this artwork piece to represent the “negativity that love can cause�. To accomplish this, she chose the heart stress related protein p38 MAPK. Using painting in oil and surrealist techniques, she was able to capture the heart shaped nature of p38 and convey how love and stress are intertwined with each other.
View the artwork in the virtual
Further reading
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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC20087/
Written by: Cristian Escobar
