Signal Transduction Biochem 528
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How can a cell detect a molecule that cannot cross its membrane?
Through transmembrane receptor proteins that recognize and bind the molecule.
What is signal transduction?
The process of converting an extracellular signal into an intracellular response.
What is the role of transmembrane receptor proteins?
They bind extracellular signaling molecules and trigger a response inside the cell.
What is a common characteristic of all organisms?
The dynamic ability to constantly coordinate their activities with environmental changes. All cells respond to their extracellular environment
What three steps must a cell perform to respond to environmental changes?
Sense changes in the local environment.
Process the information.
Produce a specific response.
What are the two types of cell signaling?
Intercellular signaling and intracellular signaling.
What is intercellular signaling?
Communication between different cells
What is intracellular signaling?
Communication and transmission of signals within a cell.
What is signal transduction?
The process by which a chemical or physical signal is transmitted through a cell as a series of molecular events.
What are the four stages of cell signaling
Reception
Transduction
Response
Resetting/Recycling (optional)
What occurs during reception?
A signaling molecule binds to a receptor, allowing the cell to detect the signal.
What occurs during transduction?
Binding of the signaling molecule causes a change in the receptor protein, initiating intracellular signaling.
What occurs during the response stage?
The change in the receptor triggers a specific cellular response.
What occurs during resetting/recycling?
The cell and receptor return to their original states.
Which stage of cell signaling is optional?
Resetting/Recycling.
What is a ligand?
A signaling molecule (stimulus) that binds to a receptor.
Where can ligand-receptor binding occur?
On the plasma membrane or intracellularly.
When does ligand binding occur on the plasma membrane?
When the ligand cannot cross the plasma membrane.
When does ligand binding occur intracellularly?
When the ligand is already inside the cell or is small/hydrophobic enough to cross the plasma membrane.
What is an example of a ligand that binds to an intracellular receptor?
Steroid hormones, because they are hydrophobic and can cross the plasma membrane
What are receptors typically made of?
Proteins, which are polymers of amino acids.
What are the three main domains of a transmembrane receptor?
Hydrophilic extracellular domain
Hydrophobic transmembrane (TM) domain
Hydrophilic intracellular domain
What is the function of the extracellular domain of a transmembrane receptor?
Ligand binding (reception).
What is the function of the transmembrane (TM) domain
The hydrophobic domain spans the plasma membrane and anchors the receptor.
What is the function of the intracellular domain of a transmembrane receptor?
Effector binding and signal transduction.
Why is the transmembrane domain hydrophobic?
Because it interacts with the hydrophobic interior of the phospholipid bilayer
How many transmembrane domains must a transmembrane receptor have?
At least one hydrophobic transmembrane domain.
How many times do receptor tyrosine kinases (RTKs) cross the plasma membrane?
Once (they have one transmembrane domain)
What type of enzyme domain do RTKs contain?
A built-in cytoplasmic kinase domain that phosphorylates tyrosine amino acids.
What must RTKs do to become functional?
Dimerize (two RTK monomers come together).
What is cross-phosphorylation in RTKs?
The kinase domain of each RTK monomer phosphorylates tyrosine residues on the other receptor.
Why is phosphorylation important in RTK signaling?
It creates recognition/binding sites for scaffolding or effector proteins.
What is the general sequence of RTK activation?
Dimerization → Cross-phosphorylation → Recruitment of scaffolding/effector proteins → Intracellular signaling.
How many transmembrane domains do G protein-coupled receptors (GPCRs) have?
7 transmembrane domains
Where are the N-terminus and C-terminus of GPCRs located?
N-terminus: Extracellular
C-terminus: Intracellular
What proteins bind to the intracellular side of GPCRs?
G proteins, which transduce signals from GPCRs.
Why are G proteins called G proteins?
Because they bind guanine nucleotides (GDP and GTP).
What is the function of G proteins in GPCR signaling?
To transmit signals from the activated GPCR to intracellular signaling pathways.
What are protein domains?
Domains are distinct functional and/or structural units in a protein. Usually they are responsible for a particular function or interaction, contributing to the overall role of a protein.
What is the function of channel proteins?
They form hydrophilic pores across membranes that allow specific molecules or ions to pass through
What are the characteristics of channel protein pores?
They are narrow and highly selective.
What is the difference between pores and channels?
Pores: Tend to remain open.
Channels: Typically gated (open and close in response to stimuli).
What is a common example of channel proteins?
Ion channels.
How many ions can pass through an open ion channel per second?
Up to 100 million ions.
What are the three types of gated ion channels?
Voltage-gated channels
Mechanically gated channels
Ligand-gated channels
What triggers voltage-gated ion channels to open or close?
Changes in voltage across the membrane.
What triggers mechanically gated ion channels to open or close?
Mechanical stress, such as pressure or stretching.
What triggers ligand-gated ion channels to open or close?
The binding of a specific ligand
What forms can ligands take?
Proteins, ions, and lipids.
Where do extracellular ligands bind?
Outside the cell, to receptors on the plasma membrane.
Where do intracellular ligands bind?
Inside the cell, to intracellular receptors.
Where can ligands be produced?
By other tissues, neighboring cells, or the same cell they act on.
Can a cell produce a ligand that triggers a response in itself?
Yes, a cell can produce a ligand that binds to its own receptors and triggers a response (autocrine signaling).
What is endocrine signaling?
Long-range signaling in which signals travel through the bloodstream to distant target cells.
What are the characteristics of endocrine signaling?
Typically produces a slow response with long-lasting effects.
What is paracrine signaling?
Short-range signaling in which signals act locally on nearby cells.
What are the characteristics of paracrine signaling?
Produces quick, short-lasting responses because signaling molecules are rapidly degraded.
What is autocrine signaling?
Signaling in which a cell releases a ligand that binds to receptors on itself or similar cells.
Which type of signaling uses the bloodstream to transport signals?
Endocrine signaling
Which type of signaling typically produces quick, short-lasting responses?
Paracrine signaling
What are hormones and what type of signaling do they use?
Involved in homeostasis; endocrine signaling.
What are growth factors and what type of signaling do they use?
Stimulate growth; endocrine, paracrine, or autocrine signaling.
What are cytokines and what type of signaling do they use?
nvolved in immune responses; mainly paracrine and autocrine, but can be endocrine.
What are neurotransmitters and what type of signaling do they use?
Stimulate neurons; paracrine signaling.
What happens when a receptor binds to its ligand?
The receptor changes conformation (shape), activating intracellular processes.
What types of proteins are typically activated during signal transduction?
Enzymes, including kinases, phosphatases, and hydrolases.
What is the function of a kinase?
Phosphorylates other molecules (adds a phosphate group).
What is the function of a phosphatase?
Dephosphorylates other molecules (removes a phosphate group).
What is the function of hydrolase enzymes?
Hydrolyze GTP to GDP or ATP to ADP.
What are second messengers?
Intracellular signaling molecules generated downstream of primary effectors that relay signals within the cell.
What are three examples of second messengers?
Cyclic AMP (cAMP), inositol trisphosphate (IP3), and diacylglycerol (DAG).
Cyclic AMP (cAMP), inositol trisphosphate (IP3) and diacylglycerol (DAG) are all what?
second messangers
What are the four possible effects of post-translational modifications?
Switch a protein on.
Switch a protein off.
Change a protein's location within the cell.
Target a protein for degradation.
What introduces post-translational modifications to signaling proteins?
Enzymes
What is a phosphate transfer reaction?
The transfer of a phosphate group from a donor (e.g., ATP) to an acceptor molecule
Where is the phosphate group commonly transferred during protein phosphorylation?
To a hydroxyl (-OH) group on an amino acid.
Is phosphate transfer a hydrolysis reaction? Why or why not?
No, because it does not involve the addition or loss of water.
What commonly acts as the phosphate donor in phosphorylation reactions?
ATP
What is isoprenylation?
A post-translational modification involving the addition of a hydrophobic lipid group to a protein
What is the main function of isoprenylation?
To help target and anchor proteins to cell membranes.
When does isoprenylation typically occur?
During the normal post-translational processing of proteins.
Why is lipid addition important for signaling proteins?
It brings membrane-associated proteins close to their effectors.
What is an example of isoprenylation?
Farnesylation of Ras proteins.
What is farnesylation of Ras proteins?
A post-translational modification in which a hydrophobic farnesyl lipid group is added to Ras.
What enzyme is responsible for farnesylation of Ras?
Farnesyltransferase
How does farnesylation affect Ras proteins?
It helps anchor Ras to the inner surface of the plasma membrane.
Why is farnesylation important for Ras signaling?
It allows Ras to associate with the membrane and interact with signaling proteins involved in signal transduction.
What is the sequence of Ras farnesylation?
Ras synthesis → Farnesyl group addition → Membrane association → Signal transduction
What is Ras, and what does it do?
Ras is a small G protein that acts like an ON/OFF switch during cell signaling.
Ras-GDP= OFF
Ras- GTP= ON
Why does Ras need to be on the membrane?
Because many proteins that activate Ras are located at or near the plasma membrane.
What are GTPases?
Enzymes that bind to and hydrolyze GTP molecules.
What is another name for GTPases?
Guanine nucleotide-binding proteins (G proteins).
What type of enzymes are GTPases?
Hydrolase enzymes.
What reaction do GTPases catalyze?
Hydrolysis of GTP → GDP + inorganic phosphate (Pi)
What is the role of GTP hydrolysis in G protein signaling?
It typically switches the G protein from its active (GTP-bound) state to its inactive (GDP-bound) state.
What are second messengers?
Small molecules that are enzymatically generated and transmit signals within a cell.
What is the function of second messengers?
To relay intracellular signals during signal transduction.
What enzymes synthesize cyclic nucleotide second messengers?
Cyclases
What is an example of a second messenger produced by a cyclase?
Cyclic AMP (cAMP), produced by adenylyl cyclase.
What is cyclic AMP (cAMP)?
An intracellular second messenger involved in signal transduction.