Cell Signaling - General Flashcards
Define types of signaling between cells and explain them briefly.
Signaling molecule and respective recognition receptor
- contact dependent (signal molecule of one cell and receptor of another cell)
- paracrine (secretion of signal molecule by one cell to the surrounding and receptor recognition on neighbouring cells)
- autocrine (self stimulation, signaling molecule and a receptor is carried by the same cell, community effect)
- endocrine (via bloodstream)
- synaptic (neuronal signaling)
Important for survival, differentiation, division, death, movement, cell shape, trigger/halt of metabolic processes and gene expression
Signal or combination of signals
Explain protein domain and motif.
Protein domain: substructure produced by any part of the polypeptide that can fold independently into a compact stable structure . Modular units from which many proteins are constructed . Domains often have specific functions within the full length protein.
-SH3 domain, small kinase domain
Protein motif : central core or part of domain is designated as protein fold or protein motif . More than 1000 different folds are known.
-helix-turn-helix
Name protein posttranslational modifications.
Regulatory principles that confer new capabilites on proteins
- Methylation
- Acetylation
- Carboxylation
- Hydroxylation
- Glycosylation
- Addition of fatty acids or isoprenoid groups
- Phosphorylation: Phosphoserine, Phosphothreonine, Phosphotyrosine
- Protein trimming and cleavage
Define allostery.
Allosteric conformational changes can be transmitted over large distances along the polypeptide chain. Most proteins.
How can signal be relayed downstream?
- Relay proteins pass on the message to the next signaling component in the chain.
- Amplifier proteins (enzymes or ion channels) greatly increase the signal they receive , either by producing small second messengers or by activating downstream intracellular signaling proteins. Multiple amplification s teps in a relay chain are called signaling cascades
- Transducer proteins convert the signal into a different form
- Bifurcation proteins spread the signal from one signaling pathway to another. Often form junctions that link different signaling cascades.
- Integrator proteins receive signals from two or more signaling pathways and integrate them before relaying a signal onward.
- Messenger proteins carry the signal from one part of the cell to another, e.g. from the cytosol to the nucleus.
- Latent gene regulatory proteins are activated at the cell surface by activated receptors and then migrate to the nucleus to stimulate gene transcription.
- Transcription factors are activated in the nucleus.
- Modulator proteins modify the activity of intracellular signaling proteins and thereby regulate the strength of signaling along the pathway.
-Adaptor proteins link one signaling protein to another,
without themselves conveying the signal.
- Anchoring proteins maintain specific signaling proteins at precise locations in the cell by tethering them to a membrane or the cytoskeleton.
- Scaffold proteins are adaptor and/or anchoring proteins that bind multiple signaling proteins together in a functional complex and often hold them at a specific location.
Explain activation by phosphorylation and by GTP/GDP
-phosphorylated - active
-dephosphorylated - inactive
(usually)
- kinase - phosphorylates
- phosphatase - dephosphorylates
Allosteric conformational change of a protein so novel binding surface for protein interactions is revealed / assembly and disassembly of protein complexes is regulated.
- serine/threonine protein kinases
- tyrosine protein kinases
- mixed
G-Proteins: trimeric GTP binding proteins, small monomeric GTP binding proteins and serpentine receptors
- GTP - active
- GDP - inactive
- GAP - GTPase activating protein
- GEF - GDP-GTP exchange factors
- GDI - GDP dissociation inhibitor
Name three small and large intracellular signaling molecules.
small: cAMP, cGMP, Ca2+
large: kinase, phosphatase, dehydrogenase… enzymes
How are Src-type proteins activated?
3 domains: SH2, SH3 and kinase domain
Inactive - SH2 is phosphorylated
phosphatase removes Pi from SH2
conformation changes and binding of the kinase domain and SH domains disrupted
tyrosine of the kinase domain is phosphorylated w/kinase
Nef protein binds SH3
How do receptors generally relay signal?
Upon ligand binding:
- Receptor via scaffolding and adaptor proteins recruit enzymes and relay the signal downstream
- Receptor autophosphorylate itself and recruits proteins which relay signal downstream
- Receptor activates PI-3 kinase and phosphorylates phosphatidylinositol
- Receptor activates phospholipase C which fragments the phospholipid into tail and head, both serve as a signal
How do smooth muscle cells contract and relax? What other gaseous molecules relax muscle cells?
1) Activated nerve cells release acetylcholine and binds to receptors on endothelial cells which activate NO synthase which convert arginine -> NO.
2) NO is difused rapidly across the membrane and binds to guanylyl cyclase which converts GTP to cGMP and relaxes the smooth muscle cells.
3) cGMP phosphodiesterase rapidly degrades cGMP.
- Nitroglycerin - Angina, pain from inadequate blood flow in heart - needs relaxation
- Viagra - inhibits cGMP phosphodiesterase
CO also stimulates guanylyl cyclase
What are two major classes of receptors?
- Intracellular Receptors
- Nuclear Receptor Family
- Cell Surface Receptors
- Enzyme linked R. (monomeric or dimeric ligand)
- G Protein linked R.
- Ion Channel linked R.
Define nuclear receptor family ligands with examples.
Small non gaseous hydrophobic molecules that diffuse directly across membranes . They bind to their intracellular receptors , which in turn are activated to stimulate transcription in the nucleus. Persist in the blood for hours (steroids) or days (yhyroids). Mediate responses that are longer lasting.
- Steroide hormones
- Thyroid hormones
- Retinoids
- Vitamin D
The activated receptors bind directly to specific DNA sequences in the promoters of target genes and regulate their rate of transcription. Upon ligand binding inhibitory proteins are dismissed from the receptors and replaced by transcriptional coactivators. Many regulatory proteins along the ligand itself is required.
1) early primary response
2) delayed secondary response from the primary one, primary response also shuts off the early primary response genes
How are G-protein receptors called? How are G-proteins activated? How are G-protein receptors turned off? How is G-protein turned off?
G-protein receptor - serpentine, pass 7 times through PM
Upon ligand binding to a serpentine receptor, alpha subunit of a trimeric G-protein w/ GDP gets exchanged for GTP, changes conformation and releases beta-gama subunit, alpha subunit then activates/inhibits enzyme or ion channel activity.
Upon ligand binding to a serpentine receptor, G-protein linked receptor kinase (GRK, like PKA and PKC) phosphorylate the receptor so arrestin can bind. Receptor is endocyted and degraded.
Upon binding the membrane target protein that relays signal onward, regulator of G-protein signaling (RGS) acts as GAP and activates the GTPase activity of alpha subunit and cleaves GTP to GDP. Alpha subunit dissociates from the membrane target protein and reassebles with beta-gama subunit.
Trimeric G-proteins and adenylyl cyclase. What does cAMP do?
Activation/inhibition of Adenylyl Cyclase rather than inhibition of Phosphodiesterase
Both, alpha and beta-gamma subunits can regulate adenylyl cyclase, but mostly the alpha subunit
- Stimulatory G proteins (Gs): activates adenylyl cyclase
- Inhibitory G protein (Gi): can inhibit adenyly cyclase but mainly regulates ion channels
cAMP: directly regulate certain types of ion channels, activating cAMP dependent protein kinase Protein Kinase A (PKA).
- PKA Type I: cytosol
- PKA Type II: membranes (PKA anchoring proteins)
PKA = regulatory subunits + kinase subunit
1) Regulatory subunit + cAMP = dissociation and nucleus entering
2) Rapid response: Skeletal muscle activated PKA phosphorylates enzymes involved in glycogen metabolism, which results in glycogen breakdown to glucose and inhibition of glycogen synthesis
3) 2. Slow and long term responses: PKA phosphorylates CREB which together with a CREB-binding protein (CBP, histone acetyl transferase) bind to creb binding element on the DNA and activate transcription
