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Protein Phosphorylation

Protein Phosphorylation

Proteins are essential in all living systems. They perform a wide range of functions especially in catalyzing biochemical reactions that are vital to metabolism. Since they are involved in different biochemical processes, their regulation in cells is important. One way to regulate proteins and their function is through protein phosphorylation.

Here, we will define protein phosphorylation and discuss the mechanisms behind it. We will also discuss how it relates to cell signaling and signal transduction as well as other cellular processes like protein degradation.

Protein phosphorylation definition

Protein phosphorylation is a form of post-translational modification wherein a phosphate group (PO4) is reversibly attached to an amino group using a protein kinase. Since protein phosphorylation is a reversible process, a protein can return to its original confirmation and activity once the phosphate group is removed. This reverse reaction is called dephosphorylation, and it is catalyzed by enzymes called protein phosphatases.

A protein kinase is an enzyme that takes phosphate groups from adenosine triphosphate (ATP) and attaches it to a protein.

Protein phosphorylation mechanism

So how exactly does protein phosphorylation work? Take a look at Figure 1 below.

Protein phosphorylation Figure 1: Mechanism | StudySmarterFigure 1. In protein phosphorylation, a protein kinase transfers a phosphate group (PO4) from an ATP molecule and added to a protein. A protein phosphatase can reverse this process by removing the phosphate group.

The terminal phosphate group of an ATP molecule is removed and transferred to a polar R group of a protein—usually serine, threonine or tyrosine and sometimes histidine.

The polar amino acid contains a charged -OH group which is involved in a nucleophilic attack to the terminal phosphate group of ATP. The attack leads to the transfer of a phosphate group to the amino acid side chain.

Protein phosphorylation function

The addition of a phosphate group alters the proteins’ stability, function, subcellular activity and enzymatic activity. Because a phosphate group contains two negative charges, a protein that undergoes protein phosphorylation will have a change in charge, causing the ligand-binding of the protein to recruit positively-charged amino acid side chains.

The attachment of the phosphate group also results in the change in structure of binding, either making it more available for other proteins or blocking it from protein-binding interactions.

Protein phosphorylation plays a central role and is ubiquitous in different cellular processes. Phosphorylation is involved in cellular signaling that mediates cell proliferation, apoptosis, protein transport and degradation. In the following section, we will discuss the role of protein phosphorylation in cell signaling--particularly in signal transduction, in protein degradation, and in neurotransmission.

Protein phosphorylation example 1: cell signaling

Recall that cell signaling is the process in which a signaling molecule called a ligand attaches to a receptor protein inside or on the surface of a target cell, leading to a specific cellular function or response like cell proliferation and cell death.

While some ligands such as steroid hormones can permeate the hydrophobic interior of the plasma membrane, then bind to intracellular receptors in the cytoplasm and directly interact with DNA, other ligands such as hydrophilic amino acid-derived hormones cannot.

Ligands that cannot pass through the plasma membrane typically interact with cell-surface receptors that transmit the signal to other receptor proteins or messengers through a process called signal transduction, covered in the next section.

Protein phosphorylation example 2: signal transduction

To regulate signal transduction, phosphorylation usually acts as an on/off switch for a lot of cell-surface receptors and its downstream signaling: these proteins are activated by adding one or more phosphate groups.

Signal transduction is the transmission of extracellular signals to intracellular signals initiated by cell-surface receptors.

In a signaling pathway, we refer to the interactions that take place prior to a certain point as upstream events while interactions that take place after that specific point as downstream events.

Many signaling pathways involve multiple protein kinases that create a phosphorylation cascade. For the signal to be transmitted, protein kinases trigger phosphorylation one after another, each time causing shape change in the phosphorylated protein.

The shape change is caused by the interaction of the phosphate groups with the protein’s charged or polar amino acids. The change in shape modifies the protein’s function, thereby activating it. This provides the mechanism for “switching on” the signal transduction pathway.

Alongside protein kinases, protein phosphatases are also present in the phosphorylation cascade. Protein phosphatases dephosphorylate or remove phosphate groups from proteins, thereby inactivating them. This provides the mechanism for “switching off” the signal transduction pathway when the signal is gone. Dephosphorylation also makes protein kinases available for succeeding signals.

As such, the combination of phosphorylation and dephosphorylation acts as a molecular switch that activates or inactivates cellular activities as required. At any one time, the activity of a protein regulated by phosphorylation is determined by how many active kinase molecules and active phosphatase molecules a cell contains.

Let’s look at a mitogen-activated protein kinase (ERK-MAPK Signaling Pathway) as an example (Fig. 2). This pathway is activated by a cascade of phosphorylation events and is important in a variety of cellular processes like cellular proliferation, differentiation, apoptosis and stress response.

Protein Phosphorylation Figure 2: ERK-MAPK Signaling Pathway | StudySmarterFigure 2. The ERK-MAPK Signaling Pathway is activated by a cascade of phosphorylation events.

First, a ligand such as an epidermal growth factor (EGF) would attach to a receptor-linked tyrosine kinase epidermal growth factor receptor (EGFR). The binding of EGF to EGFR triggers the tyrosine kinase activity that leads to EGFR phosphorylation. Once EGFR is phosphorylated, it leads to a cascade of other kinases. Activated Ras protein also activates a Raf kinase which in turn phosphorylates a MAPK/ERK kinase. Once activated, MEK would activate other MAPKs downstream.

This is an example of a protein signaling cascade in which Raf, MEK and ERK are part of the MAPK signaling cascade. As you can see, phosphorylation is a key event in regulating the whole cascade. This is especially important since the MAPK signaling pathway plays a significant role in a wide range of cellular processes.

So what happens when this pathway is left uncontrolled? Abnormal activity in this signaling pathway could lead to multiple diseases, including cancer. In cancer, most intracellular signaling pathways are dysregulated. The dysregulation of MAPK signaling in cancer is linked to uncontrolled cellular proliferation and resistance to chemotherapy. This is why drugs that try to target and control cell growth are used for cancer.

Protein phosphorylation example 3: degradation

The accumulation of proteins, especially misfolded proteins, is not favorable since this accumulation can lead to pathological diseases, such as Alzheimer's, ALS, and Huntingtons disease. To prevent damage, proteins need to be degraded by proteasomes. There are different mechanisms by which proteasomes degrade protein and protein phosphorylation is an essential part of these.

  • Generally for protein degradation to occur, the activity of the enzyme ubiquitin ligase is turned on first by phosphorylating it. Once ubiquitin ligase is activated by phosphorylation, it can now form a multi-subunit ubiquitin ligase that can cause the degradation of proteins.

  • Another way of degradation is for proteins to create a degradation signal. A degradation signal is created by phosphorylating a specific site on a protein. Once phosphorylated, a degradation signal that is typically hidden within a protein is revealed.

Protein phosphorylation example 4: neurotransmitters

Another example of protein phosphorylation is seen in our nervous systems. Phosphorylation is important to transfer information in neurotransmitters, the ligands responsible for carrying a signal from one neuron (or nerve cell) to a target cell in the body.

Enzymes that synthesize neurotransmitters need to be phosphorylated for synaptic transmission. In order to regulate this transmission, ion channels and receptors are phosphorylated. Upon phosphorylation, there is a change in conformation which switches the ion channel on and off.

Such is the case of a cation channel in noradrenergic neurons of the locus coeruleus (a nucleus in the brain stem) which is activated via phosphorylation of the channel by protein kinase A.

On the other hand, the phosphorylation of other channels such as voltage-gated Na+, K+ and Ca2+ channels alters the probability of the channels opening or closing in response to changes in membrane potential.

Protein Phosphorylation - Key takeaways

  • Protein phosphorylation is a form of post-translational modification wherein a phosphate group (PO4) is reversibly attached to an amino group using a protein kinase.
    • A protein kinase is an enzyme that takes phosphate groups from adenosine triphosphate (ATP) and attaches it to a protein.
  • A protein can return to its original confirmation and activity once the phosphate group is removed through dephosphorylation.
    • Dephosphorylation is catalyzed by enzymes called protein phosphatases.
  • To regulate signal transduction, phosphorylation usually acts as an on/off switch for a lot of cell-surface receptors and its downstream signaling: these proteins are activated by adding one or more phosphate groups.

References

  1. Reece, Jane B., et al. Campbell Biology. Eleventh ed., Pearson Higher Education, 2016.
  2. Nestler EJ, Greengard P. Neuronal Phosphoproteins. In: Siegel GJ, Agranoff BW, Albers RW, et al., editors. Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th edition. Philadelphia: Lippincott-Raven; 1999. Available from: https://www.ncbi.nlm.nih.gov/books/NBK28010/
  3. Zedalis, Julianne, et al. Advanced Placement Biology for AP Courses Textbook. Texas Education Agency.
  4. Cordover E, Minden A. Signaling pathways downstream to receptor tyrosine kinases: targets for cancer treatment. J Cancer Metastasis Treat 2020;6:45. http://dx.doi.org/10.20517/2394-4722.2020.101

Frequently Asked Questions about Protein Phosphorylation

Phosphorylation alters the proteins’ stability, function, subcellular activity and enzymatic activity.

Because a phosphate group contains two negative charges, a protein that undergoes protein phosphorylation will have a change in charge, causing the ligand-binding of the protein to recruit positively-charged amino acid side chains. 


The attachment of the phosphate group also results in the change in structure of binding, either making it more available for other proteins or blocking it from protein-binding interactions.

Processes that generally require protein phosphorylation include cellular signaling that mediates cell proliferation, apoptosis, protein transport and degradation. 

To regulate the activity of proteins, the combination of phosphorylation and dephosphorylation usually acts as an on/off switch by adding or removing phosphate groups.

The addition of a phosphate group alters the proteins’ stability, function, subcellular activity and enzymatic activity by changing its charge and structure.

Methods for measuring the phosphorylation of proteins  include kinase activity assays and mass spectrometry.

Final Protein Phosphorylation Quiz

Question

What is protein phosphorylation?

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Answer

Protein phosphorylation is a form of post-translational modification wherein a phosphate group (PO4) is reversibly attached to an amino group using a protein kinase. 

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Question

What enzyme catalyzes protein phosphorylation?

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Answer

Protein kinase

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Question

What enzyme catalyzes protein dephosphorylation?

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Answer

Protein phosphatases

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Question

A protein kinase is an enzyme that takes phosphate groups from _____ and attaches it to a protein.

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Answer

Adenosine triphosphate

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Question

A protein can return to its original confirmation and activity once the phosphate group is removed through ____.

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Answer

Dephosphorylation

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Question

Describe the role of phosphorylation in signal transduction.

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Answer

To regulate signal transduction, phosphorylation usually acts as an on/off switch for a lot of cell-surface receptors and its downstream signaling: these proteins are activated by adding one or more phosphate groups. 

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Question

In phosphorylation, the terminal phosphate group of an ATP molecule is removed and transferred to the ____ of a protein.

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Answer

R group

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Question

A protein that undergoes protein phosphorylation will have a change in charge, causing the ligand-binding of the protein to recruit _____-charged amino acid side chains

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Answer

positively

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Question

What is a phosphorylation cascade?

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Answer

It is when protein kinases trigger phosphorylation one after another, each time causing shape change in the phosphorylated protein.


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Question

How is protein activity "switched on"?

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Answer

Phosphorylation causes the protein's shape to change, thereby activating it. This provides the mechanism for “switching on” the signal transduction pathway.

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Question

How is protein activity "switched off"?

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Answer

Protein phosphatases dephosphorylate or remove phosphate groups from proteins, thereby inactivating them. This provides the mechanism for “switching off” the signal transduction pathway when the signal is gone. 

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Question

How is the activity of a protein regulated?

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Answer

At any one time, the activity of a protein regulated by phosphorylation is determined by how many active kinase molecules and active phosphatase molecules a cell contains.

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Question

To prevent damage, proteins need to be degraded by ____.

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Answer

proteasomes

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Question

Generally for protein degradation to occur, the activity of the enzyme _____ is turned on first by phosphorylating it. 

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Answer

ubiquitin ligase

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Question

How is a degradation signal created?

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Answer

A degradation signal is created by phosphorylating a specific site on a protein. Once phosphorylated, a degradation signal of a protein that is typically hidden is revealed. 

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