Podcast
Questions and Answers
What key step occurs after the activation of Galpha in transmembrane signalling?
What key step occurs after the activation of Galpha in transmembrane signalling?
Which process requires the enzyme N-myristoyltransferase for membrane association?
Which process requires the enzyme N-myristoyltransferase for membrane association?
Which lipid modification is associated with dynamic membrane association?
Which lipid modification is associated with dynamic membrane association?
Which domain binds specifically to phosphatidylinositol in signalling proteins?
Which domain binds specifically to phosphatidylinositol in signalling proteins?
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What is the function of C2 domains in protein kinase C (PKC)?
What is the function of C2 domains in protein kinase C (PKC)?
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Which statement best describes lipid modification through isoprenylation?
Which statement best describes lipid modification through isoprenylation?
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What characterizes heterotrimeric G proteins in terms of structure?
What characterizes heterotrimeric G proteins in terms of structure?
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The key step in comparing signalling via oligomerization versus conformational change is that both ultimately regulate what?
The key step in comparing signalling via oligomerization versus conformational change is that both ultimately regulate what?
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What is the primary function of lipid binding domains in proteins?
What is the primary function of lipid binding domains in proteins?
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What is a significant structural feature of G protein-coupled receptors (GPCRs)?
What is a significant structural feature of G protein-coupled receptors (GPCRs)?
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Which class of GPCRs is known for interacting with polypeptide hormones?
Which class of GPCRs is known for interacting with polypeptide hormones?
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What role do intracellular loops and the C-terminus serve in GPCRs?
What role do intracellular loops and the C-terminus serve in GPCRs?
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Which modification can affect the folding and trafficking of GPCRs?
Which modification can affect the folding and trafficking of GPCRs?
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Why are signalling proteins designed to be regulated rather than efficient at turnover?
Why are signalling proteins designed to be regulated rather than efficient at turnover?
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Which characteristic is key for membrane fluidity and conformation affecting protein interactions?
Which characteristic is key for membrane fluidity and conformation affecting protein interactions?
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What type of receptor primarily interacts with the WNT signaling pathway?
What type of receptor primarily interacts with the WNT signaling pathway?
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Study Notes
Transmembrane Signalling: Key Players and Mechanisms
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Heterotrimeric G proteins:
- Possess post-translational modifications (PTMs)
- Contain a lipid-like molecule
- Elongate into alpha, beta, and gamma subunits
- Multidomain proteins with domains interacting with membrane components and specific lipid compounds
Membrane Association: PTMs
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PTMs:
- Modifications attached to proteins influencing stability
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Myristoylation:
- C14 saturated chain from myristic acid attached to the N-terminal amide
- Stable modification
- Requires N-myristoyltransferase enzyme
- Mediates membrane association and protein-protein interactions
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Palmitoylation:
- C16 saturated chain attached to a cysteine residue via a thioester linkage
- Dynamic modification
- Primarily found on the cytoplasmic face of the plasma membrane
- Regulated membrane association
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Isoprenylation:
- Thioester bond (stable) to a cysteine residue
- Attached by farnesyl- or geranylgeranyl transferase enzymes
- Recognizes the hydrophobic Caax box near the C-terminus of the protein
- Found in GPCRs and canonical membrane signaling proteins
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Glycosylphosphatidyl-inositol (GPI):
- Attached to the C-terminus
- Commonly found in extracellular proteins
Membrane Association: Domain Interactions
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Phospholipase C (PLC) and Protein Kinase C (PKC):
- Contain multiple membrane-association domains
- Pleckstrin homology domain (PH): binds to phosphatidylinositol
- C2 domain: binds to phospholipid serine
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Protein kinase C domain:
- C1 domains: bind to diacylglycerol
- C2 domains: bind to phospholipid serine
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The Pleckstrin homology domain:
- Mixed alpha-beta fold
- Binding pocket enriched in positively charged residues
- Recognizes specific inositol modifications (e.g., 1,2,3,gamma)
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The C2 domain:
- Eight-stranded beta sandwich
- Loops bind to Ca2+
- Enables Ca2+-dependent binding to lipids
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The C1 domain of PKC:
- Small cysteine-rich domain
- Hydrophobic residues bind to and recognize diacylglycerol
Signal Transduction: GPCRs and Conformational Changes
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GPCRs:
- 7 transmembrane helices
- Intracellular loops and C-terminus regulate G-protein recruitment
- Loops 3-4 and 5-6 interact with alpha subunits
-
PTMs:
- N-glycosylation influences folding and trafficking of extracellular domains
- Disulfide bonds between helices
- Lipidation in the C-terminal tail
-
Lipid Modification:
- Mediates Beta/gamma subunit interactions
GPCR Families
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5 major GPCR families:
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Class A (Rhodopsin family):
- Small molecule ligands
- Largest class
- Example: Beta-adrenergic receptor
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Class B (Secretin family):
- Polypeptide hormones
- Example: Glucagon
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Class C (Glutamate family):
- Orthosteric binding site
- Additional domain
- Example: Glutamate
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Class F (Frizzled):
- WNT signaling
- Adhesion
- Primarily orphan receptors
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Dynamic bundles of hydrophobic helices:
- Enriched in hydrogen bonds in extracellular loops
- Enriched in hydrophobic residues within the membrane
- Understand how ligands, effector proteins, and therapeutics modulate GPCR activation and stability
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Class A (Rhodopsin family):
Membrane Transport: Signaling Proteins and Localization
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Membrane transport is vital for:
- Metabolism
- Physiology
- Signaling
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Protein signaling is regulated by:
- Localization
- Activity
- Signaling proteins are optimized for regulation
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Membrane reduces dimensions from 3D to 2D:
- Facilitates interactions that are less likely to occur in solution
- Influences signal transduction
Signal Transduction: Oligomerization vs. Conformational Change
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Single-pass ligand-induced changes in localization:
- Involves delocalized inactive structures
- Ligand binding brings receptors into an oligomer
- Oligomer forms the active site
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Changes in conformation:
- Often facilitated by multi-pass type membrane proteins
- Proteins or small molecules can trigger conformational change
- Monomeric/dimeric states often determine inactive/active forms
Signaling by Conformational Change: GPCRs
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7 transmembrane helices:
- Intracellular loops and C-terminus mediate G-protein recruitment
- Loops 3-4 and 5-6 interact with alpha subunits
Growing GPCR Crystals
- Requires high affinity agonists to stabilize activated GPCRs
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Description
This quiz explores the key players and mechanisms involved in transmembrane signalling, focusing on heterotrimeric G proteins and their post-translational modifications such as myristoylation, palmitoylation, and isoprenylation. Understanding these processes is crucial for grasping how proteins interact with membranes and influence cellular signaling.
