Protein Covalent Modification: Phosphorylation and More

Covalent Modification

• Phosphorylation, glycosylation, methylation, and acetylation are the most common forms of covalent modification.
• Glycosylation is a post-translational modification.
• Phosphorylation occurs when a protein kinase transfers a phosphate from ATP to the hydroxyl group of a specific serine, threonine, or tyrosine amino acid on the target enzyme, causing a conformational change that makes certain enzymes more or less active.
• Dephosphorylation occurs when a protein phosphatase removes the phosphate by hydrolysis, reversing the effect of phosphorylation.
• Phosphorylation adds two negative charges and can make H-bonds.

Zymogens and Proteolytic Cleavage

• Zymogens are inactive enzymes that become active through proteolytic cleavage.
• Proteolytic cleavage is an irreversible process that activates enzymes.
• This process helps prevent enzymes from prematurely breaking down other proteins during their production or release.

Enzymes

• Enzymes are catalysts that speed up the rate of reaction by lowering activation energy.
• Enzymes regulate the rate of metabolic pathways in the body.
• Allosteric regulation involves conformational changes that affect the catalytic site, and is achieved through allosteric activators or inhibitors binding to the active catalytic site.

Allosteric Regulation

• Allosteric regulation can occur in two states: T (tense) with low affinity and R (relaxed) with high affinity.
• Adenosine diphosphate (ADP) or adenosine monophosphate (AMP) are allosteric activators of PFK1, which is activated when ATP concentration in a muscle cell decreases.
• ATP build-up inhibits PFK1.

Enzyme Regulation

• Enzyme activity can be regulated by covalent modification, such as phosphorylation of an amino acid from the kinase domain.
• Signal transduction occurs from the membrane to the signal transducer protein through covalent modification.

JAK-STAT Receptors

• JAK-STAT receptors are heterodimers, consisting of two different proteins that bind together.
• They are activated when a cytokine attaches, and JAK kinases bind to the heterodimers and phosphorylate each protein.
• Signal transduction occurs from the membrane to the signal transducer protein.

Serine-Threonine Kinase Receptors

• Cytokine dimer binds to heterodimers, and one heterodimer protein phosphorylates another, which then phosphorylates a signal transducer protein.

Protein Functions

• Hormonal proteins coordinate an organism's activities, with examples including insulin.
• Contractile and motor proteins facilitate movement, with examples including actin and myosin proteins.
• Structural proteins provide structure and support, with three types of structural proteins.

Misfolding and Chaperone Proteins

• Misfolded proteins can clump together, potentially harming cells.
• Chaperone proteins aid in correct folding by providing the right environment for proper folding.
• Misfolding can create amyloid fibrils, leading to diseases like Alzheimer's and Parkinson's.