Exam 1 Flashcards
Extracellular signaling molecules
1) are secreted or cell-surface chemical signals
2) bind to receptors
3) regulate the activity of the cell expressing the receptor
4 forms of intercellular signaling
1) contact dependent
2) paracrine
3) synaptic
4) endocrine
Contact dependent intercellular signaling
Extracellular signaling molecules must come in contact with the receptors
Paracrine intercellular signaling
Cell releases extracellular signaling molecules into the general vicinity
Synaptic intracellular signaling
Neuron to axon to target cell
Endocrine intracellular signaling
Extracellular signaling molecules released in to the blood stream to take signal gar away
Intracellular receptors
Mostly located near the nucleus
Describe intracellular receptor signaling ligands
Must be small and hydrophobic so they can cross the lipid bilary of the cell and the nuclear membrane
Second messengers
Small chemicals that serve as intercellular signaling molecules
Examples of second messengers
Ca2+, cyclic AMP, IP3 (water soluble and diffuse in the cytosol)
Diacylglycerol (lipid soluble, diffuse in the plane of the plasma membrane)
Two main molecular switches
1)Phosphorylation
2)GTP-binding proteins
Protein kinases
A molecular switch
Adds a phosphate group to specific amino acid
2 main types of protein kinases
1)Tyrosine kinase
2)Serine/threonine kinase
Protein phosphatases
Molecular switches
Removes a phosphate group
GTP-binding proteins “on” state
Protein bound to GTP
GTP-binding proteins “off” state
Protein is bound by GDP
Two main types of GTP-binding proteins
1) Large trimeric GTP-binding proteins
2) Small monomeric GTPases
What do GAPs do to GTP-binding proteins?
Turns them off
What to GEFs do to GTP-binding proteins?
Turns them on
Three types of signaling complexes
1) Scaffold protein
2) Activated receptor
3) Phosphoinositide docking sites
PH domain binding target
Phosphoinositides
PTB domain binding target
Phosphorylated tyrosine
SH2 domain binding target
Phosphorylated tyrosine
SH3 domain binding target
Proline- rich repeats
Positive feedback loop
output stimulates its own production
Negative feedback loop
output inhibits its own production
How does a long delay effect a negative feedback loop?
It causes the system to oscillate
Negative feedback turns off signal, stimulus turns the signal back on.
How do a short delay effect a negative feedback loop?
System behaves like a detector for change
Stimulus strongly turns on signal, negative feedback loop causes it to rapidly decay, stimulus turns signal back on
Delayed feed-forward
Makes and inhibitory protein before the output
Receptor Inactivation
The receptor is help inactive even as the stimulus is there
Receptor Sequestration
Endocytosis receptor goes into the cell
Receptor Destruction
lysosome kills receptor
GPCR structure
Single polypeptide chain
Transverses the plasma membrane 7 times
Deep ligand binding site
What is needed for the receptor to truly be a GPCR?
Trimeric G-protein to relay signals
Active G-protein is bound to…
GTP
Inactive G-protein is bound to….
GDP
What is the role of adenylyl cyclase in cAMP signaling?
Produces cAMP
Stimulatory G proteins
Actives adenylyl cyclase along with Ca2+
Inhibitory G proteins
Inhibit adenylyl cyclase
cAMP phosphodiesterase
Degrades cAMP
PKA
serine/threonine kinase
With 4 subunits
IP3
Second messenger
Water soluble, diffuse through the membrane
DAG
Second messenger
Lipid soluble
Phospholipase C
PRODUCES IP3 and DAG
Activated by Gq G-protein
Why is Ca2+ such an important second messenger?
There is a huge concentration gradient that will drive Ca2+ into the cytosol
Regulatory subunits of PKA
anchor PKA to things with in the cell
has 4 Ca2+ bindng pockets
Catalytic subunits of PKA
Undergo a conformational change and activate
Calmodulin
Most important intracellular signal
Binds 4 Ca2+
Has no enzymatic activities but binds to and activates other proteins
Enzyme coupled receptors
Transmembrane protein
Ligand binding domain on extracellular portion
Cytosolic domain is enzymatic OR associates with an enzyme
What mediates signaling of RTKs
GTPases
Ras GEFs
stimulate the dissociation of GDP
Ras GAPs
Increase the rate of hydrolysis of bound GTP
What does Ras activate?
A MAP kinases signaling module
Where does phosphorylation take place on the inositol ring?
Position 3
PIP2
Can be cleaved by phospholipase C to generate DAG and IP3
Can be phosphorylated by PI3 kinase and serve as a docking site
Cells expressing Delta become
Neural cells
Cells expressing Notch become
Epithelial cells
Delta/Notch is what kind of signaling
Contact Dependent
What happens in the absence of Wnt?
Beta-catenin is sequestered in a degradation complex, and gets broken down
Is Frizzled a GPCR?
NO! There is no G-protein associated with
What happens in the Hedgehog pathway when Hedgehog is absent? (3)
-Patched keeps Smoothened inactive
-The Ci protein is proteolytically processed
-The cleaved tail of the Ci protein translocates to the nucleus and acts as a transcription repressor
Three major families of cytoskeleton components
Intermediate Filaments, Microtubules, Actin filaments
Actin filaments
Comprised of actin subunits and are polar
Determine shape of cell’s surface
Necessary for the whole-cell locomotion
Drives pinching of one cell into two
Describe actin subunits
Monomeric, globular proteins with ATP-binding domain (ATP can be hydrolyzed)
What does it mean for a molecule to be polar
They have a plus end and a minus end.
Describe the plus end of actin?
Barbed and polymerize quickly
Describe the minus end
Pointed and polyermize slowly
Nucleation
When two actin molecules bind relatively weakly, but the addition of a third monomer forms a trimer that is much more stable
What are the three phases to the time course of polymerization?
Lag phase, Growth phase, Equilibrium/steady state
What is the Lag phase of polymerization?
Time taken for nucleation
What is the Growth phase of polymerization?
Occurs as monomers are adding to the exposed ends of the growing filament, causing filament elongation
What is the Equilibrium/steady state of polymerization?
Reached when the growth of the polymer balances the shrinkage of polymer
How can you abolish the Lag phase?
Adding premade nuclei (seed filaments)
What is treadmilling?
When polymerization of the + end is the same rate as depolarization of the - end
What does Thymosin do?
Prevent polymerization by holding the monomers like a dragon with its treasure
What does Profilin do?
Promote polymerization by taking subunits and add them to polymer.
What does ARP 2/3 complex do?
Creates structures of branching actin filaments; nucleates filaments at the minus end (cap -)
What does Formins do?
Creates parallel bundles of actin filaments (dimmer reaches out and grabs subunits)
What do Side-binding proteins do?
Stabilize and modulate interactions with other proteins (Tropomyosin)
What do Cap-binding proteins do?
Stabilize + or - end
What Cap-binding protein binds the - end?
ARP 2/3 complex
What Cap-binding protein binds the + end?
Cap Z
What does Tropomodulin do?
Bind the - end of tropomyosin-coated filaments as a capping protein
Cofilin
Binds along ADP-bound actin and twists and weakens it
Arp2/3 complex
creates dendritic branching networks of actin filaments
What do the Gelsolin family of proteins do?
Interact with sides of filaments and cuts them
What is fimbrin?
Protein that binds with actin filaments to make parallel bundles
What are parallele bundles?
Tight packing bundles that prevent myosin II from entering the bundle and binding
What does alpha- actin in do?
Bind with actin filaments to form contractile bundles
What are contractile bundles?
Loose packing actin bundles that allow myosin II to enter the bundle and bind
What to filamin dimers do?
Allow for 3D mesh/gel to form
What does myosin consist of?
2 heavy chains and 2 light chains
Which myosin chain has globular domains?
Heavy
What creates the myosin tail?
Long AA chain
Can Myosin move if ATP is bound?
NO
Myofibril
cylindrical structures, long chain of tiny contractile units
Sarcomeres
Contractile
Protofilaments
Comprised of tubulin subunits that nis a heterodimer of Beta and Alpha tubulin
Beta tubulin
Has a GTP binding site that can be hydrolyze
Alpha tubulin
Has a GTP binding site that can not be hydrolyze
Stathmin
Prevents polymerization/ promotes depolymerization of microtuble
y-tubulin ring complex
minus end cap of microtubles
Centrosome
Microtubule organizing center
Centrioles
pair of cylindrical, barrel shaped rings of microtubules
Microtubule Associated Proteins
Stabilizes microtubules and mediate interactions with other components
MAP2
Widely spaced microtubule bundles
Tau
Closely packed microtubule bundles
Augmun
Creates branching networks of microtubules
Typically playing a major role in mitotic spindle formation
+TIPS
Associate with growing + ends and link microtubules to other structures
XMAP215
Associates with + end and accelerates /promotes polymerization
Binds to free tubulin subunits and delivers them to the + end
Catastrophe factors
Promote destabilization
Binds the end of microtubules and pries the protofilaments apart
Katanin
Cuts microtubules and promotes destabilization
Two types of motor proteins
Kinesin and Dynein
Kinesin
Motor protein that carries cargo to the PLUS end
Dynein
Motor protein that carries cargo to the MINUS end
Intermediate Filaments
made up of different elongated proteins with alpha helical domains
monomers form coiled coil dimers
Dimers form tetramers
8 tetramers form rope like filament
Do intermediate filaments have polarity
NO there is no structural polarity and no nucleotide binding sitesS
Septins
GTP binding proteins that provide scaffolding to compartmentalize membranes
Nuclear Laminins
Comprise a meshwork lining on the inner membrane of the nuclear envelope
Vimentin
Provides support in many differnt cell types
Keratin
Most diverse intermediate family
Provide mechanical strength to epithelial tissues
Neurofilaments
Present in axons of neurons
Plakins
Link intermediate filaments to the rest of the cytoskeleton
Can interact with other protein complexes
Lamellipodia actin while crawling
Actin remains stationary but undergoes treadmilling
+ ends face forward and - end attached to other actin by ARP2/3 complex
CDC42
Promotes polymerization of actin filaments and can activate WASp proteins
Bind ARP2/3 complexes and increase nucleation
RAC
Also activates WASp proteins
Increases nucleation and activates filament to create gel-like actin networks
Rho
Turns on formins to build parallel actin bundles
Inhibits cofilin stabilizes actin
