regulatory proteins

Genetic regulatory proteins bind to segments of DNA and bring about gene regulation. Non-genetic classes of regulatory proteins include those target, effector proteins that are involved in special cellular functions such as signaling as receptor proteins and pumps, adhesion, chemotaxis, cellular transport and active transport, and metabolic regulation, including enzymatic action and protein degradation.

Repressors and other regulatory proteins probably search for target sequences by binding to DNA and scanning its major groove. Most regulatory proteins recognize DNA because they can slide along it while searching for a specific target sequence. Such a search would be much slower for a protein that cannot bind DNA. [s]

Tables  Regulatory Proteins Sequences  Gene Regulation in E.coli  Second Messengers  Cell signaling  Cell Adhesion Molecules  Enzymes Function Krebs Cycle  Enzymes Cofactors of Krebs Cycle

Most gene regulation proteins are single proteins, often homodimers or homotetramers, which bind to two ligands: a. a metabolic intermediate, and b. a cis-acting gene regulation element.

Most of the known phosphorylated response regulators employ the two-component system to stimulate or repress the transcription of specific targetted genes.

Allosteric regulatory proteins alteration of metabolic pathways utilizing end product repression, enzyme induction, and catabolite repression. Like allosteric enzymes, these proteins alter their levels of activity in response to ligand-binding induced conformational (shape) changes. The allosteric or effector ligand is a small molecule that affects the active site by binding to the allosteric site. In the case of allosteric regulatory proteins, the active site is a DNA binding site, which binds, only when active, to a specific sequence of DNA. By binding to specific DNA sequences, the allosteric regulatory protein impacts levels of gene expression.

Items • allosteric enzymes • anabolism and catabolism • Control of prokaryotic gene expression • gene regulation • Interactions in Bacteria • phosphorylation • Phosphorylation switches in bacteria • phosphotransfer-mediated signaling pathways • Protein Kinase Signaling Networks • signaling gradients • signal transduction • two-component systems ••
Tables  Regulatory Proteins Sequences  Gene Regulation in E.coli  Cell signaling  Receptor Tyrosine Kinases(RTK)  Second Messengers  Phosphate-handling Enzymes  Second Messengers
 Cell signaling  Immune Cytokines  Electron Transport Chain vs Oxidative Phosphorylation  Enzymes Function Krebs Cycle  Enzymes Cofactors of Krebs Cycle  Phosphate-handling enzymes

Specific Enzymes/Types : ·· A · adenylyl (adenylate) cyclase · allosteric enzymes · AP endonuclease (Ape1) ·· C · cAMP-dependent protein kinase · cyclin-dependent kinases ·· D · DAGKs · diacyl glycerol kinases · DNA glycosylase · DNA ligase · DNA Ligase I · DNA polymerases · DNA polymerase I · DNA polymerase beta · DNase IV · · E · exonuclease 1 · exosome ·· F · focal adhesion kinases (FAKs) · Fen1 · Flap Endonuclease FEN-1 · G · guanylate cyclases · guanyl cyclase ·· H · hOGG1 · hOGG1 oxoG repair ·· I · inducible transcription factors ·· L · LigIII · · M · MAP kinase · mitogen activated protein kinases · Msh2-Msh3 · MutS, MutL, and MutH ·· O · 8-oxoguanine glycosylase · oxoG repair hOGG1 ·· P · PCNA · phosphatases · phosphodiesterases · phospolipases · phospholipase C-gamma · PLC-G · protein kinase A · protein kinase C · protein tyrosine kinases (PTKs) · receptor tyrosine kinases · R · RNA polymerase · Replication factor C · reverse transcriptase · ribozymes · RNA polymerase II · RTKs ·· S · serine/threonine kinases · spliceosomal-mediated RNA trans-splicing · SMaRT ·· T · trans-splicing ribozymes ·· U · UvrD ·· X · XRCC1 ·

Specific proteins/types : ·· C · cAMP receptor binding protein · cofactor · core histones H2A, H2B, H3, and H4 · CRE-binding protein CREB · cytokines ·· E · elongation factor EF ·· G · general transcription factors ·· H · helicases : Helicase II · heterochromatin · histone · HP1 · I · inducible transcription factors · L · · LexA repressor ·· M · mCAT2 receptor · motor proteins ·· N · nucleosome ·· P · PcG proteins · PCNA · Polycomb group · proteome ·· R · RecA · regulatory proteins · repressor proteins · Receptor Tyrosine Kinases (RTKs) · ribosomes · RPA ·· S · serine rich (SR) splicing factors · silencers · Ski7p · small nuclear ribonucleoproteins (snRNPs) · spliceosome · SR (serine rich) splicing factors ·· T · TATA binding protein · TBP · trans-acting factors · trithorax group (trxG) ·· U · ubiquitin (Ub) · UPF1 UPF2 · upstream transcription factors ·

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signal transduction

Cellular signal transduction involves the conversion of one signal or stimulus (mechanical or chemical) to another. The transduction process is usually performed by enzymes in association with second messengers.

▼ : 7TM receptors : classes of receptors : controlled activities : coupling : DAG : diacylglycerol : DGKzeta : extracellular signals : GEFs : G-protein coupled receptors : guanine nucleotide-binding protein-coupled receptors : GPCR families : GPCRs : heptahelical receptors : hormone receptors : HREs : intracellular signals : intracellular receptors : intercellular signals : IP3 : kinase inhibitors : ligands : phospholipases : phospholipids : PI3K : PKCs : protein kinases : Ras : RasGRP : receptor classes : serpentine receptors : targets for control : 7TM receptors : ▼

Extracellular signals impinge upon specialized membranous receptors. Sensory transduction involves the conversion of mechanical or chemical stimuli to cellular signals or neurophysiological signals. Intracellular signals enable communication within cells, while intercellular signals enable communication between cells.

Tables  Cell Adhesion Molecules  Cell signaling  Immune Cytokines  Receptor Tyrosine Kinases (RTKs)  Second Messengers 

Chemical signals (ligands) include :
1. neurotransmitters : acetylcholine, dopamine, epinephrine, GABA, glycine, norepinephrine, serotonin (5HT), etc.
2. hormones
3. phospholipids
4. growth factors
5. nutrients

Classes of receptors:
1. Membrane-penetrating receptors possessing/connected to intrinsic enzymatic activity:
…….a) receptor tyrosine kinases (RTKs) capable of autophosphorylation as well as phosphorylation of other substrates (incl. EGF, FGF, insulin, PDGF receptors),
…….b) tyrosine phosphatases (CD45),
…….c) guanylate cyclases (natriuretic peptide receptors),
…….d) serine/threonine kinases (activins, inhibins, bone morphogenetic proteins (BMPs), TGF-beta receptors).
…….e) receptors coupled to intracellular tyrosine kinases by direct protein-protein interactions: 'Multiprotein signaling networks create focal points of enzyme activity that disseminate the intracellular action of many hormones and neurotransmitters. Accordingly, the spatio-temporal activation of protein kinases and phosphatases is an important factor in controlling where and when phosphorylation events occur. Anchoring proteins provide a molecular framework that orients these enzymes towards selected substrates. A-kinase anchoring proteins (AKAPs) are signal-organizing molecules that compartmentalize the cAMP dependent protein kinase, phosphodiesterases, and a variety of enzymes that are regulated by second-messengers.'[s].

Phospholipases and phospholipids participate in transmission of ligand-receptor induced signals from the plasma membrane to intracellular proteins, primarily PKC, which is maximally active in the presence of calcium ion and diacylglycerol. PKC activity is mediated by receptors that are coupled to activation of phospholipase C-gamma (PLC-gamma), which contains SH2 domains that enable it to interact with tyrosine phosphorylated RTKs. PI-3K is tyrosine phosphorylated and activated by various RTKs and receptor-associated PTKs. PI-3K is activated by the PDGF, EGF, insulin, IGF-1, HGF and NGF receptors. The p85 subunit of PI-3K is activated by tyrosine phosphorylation, but only the 110 kDa subunit is enzymatically active.

Phospholipases D and A2 (PLD, PLA2) sustain the activation of PKC through their hydrolysis of membrane phosphatidylcholine (PC). Activation of PLC-gamma results in hydrolysis of membrane phosphatidylinositol bisphosphate (PIP2), which leads to an elevation of intracellular DAG and inositol trisphosphate (IP3), which interacts with intracellular membrane receptors to effect release of stored calcium ions (PKC is maximally active in the presence of second messengers, calcium ions and diacylglycerol).

Diacylglycerol (DAG) is an intracellular messenger, which accumulates transiently in cells exposed to growth factors or other stimuli. Cellular responses such as growth and differentiation are impacted by the binding of DAG to PKC, thus activating PKC. Diacylglycerol kinases (DGKs) are responsible for eliminating the function of diacylglycerol (DAG) and for producing phosphatidic acid (PA) (both molecules are connected to cancer).

DGKzeta regulates factors that promote activity of the oncogene product, Ras, the activity of which must be precisely regulated lest abnormal cellular proliferation result. An estimated 30% of human tumors have an activating mutation of the Ras gene. Guanine nucleotide exchange factors (GEFs) activate Ras by facilitating GTP binding. Abnormally high levels of the nucleotide exchange factor, RasGRP can lead to malignant transformation. RasGRP has a diacylglycerol (DAG)-binding domain and its exchange factor activity depends on local availability of the signaling molecule DAG. Diacylglycerol kinases (DGKs) remove DAG from the cell by converting DAG to PA. DGKzeta, but not other DGKs, can completely eliminate Ras activation induced by RasGRP, and diacylglycerol kinase activity is required for this mechanism.

2. Serpentine receptors, guanine nucleotide-binding protein-coupled receptors, or GPCRs, in which a characteristic trans-membrane structure spans the cell membrane seven times. Intracellular signalling is carried out by association of the neurotransmitter with G-proteins (small GTP-binding and hydrolyzing proteins), which leads to generation of second messengers. GTP-hydrolytic activity of G-proteins is regulated by GTPase activating proteins, GAPs. Ras, is a proto-oncogenic G-protein involved in carcinogenesis. Other cancer-active G-proteins include the gene products of the neurofibromatosis type-1 (NF1) susceptibility locus and the BCR locus (break point cluster region gene).

There are several families of GPCRs, including:
(a) GPCRs that modulate adenylate cyclase activity
(b) GPCRs that activate phospholipase C-gamma, leading to hydrolysis of polyphosphoinositides (such as PIP2) and generating the second messengers, diacylglycerol (DAG) and inositol trisphosphate (IP3). This class of receptors includes receptors for angiotensin, bradykinin and vasopressin.
(c) Photoreceptors coupled to a G-protein (transducin) that activates a phosphodiesterase, depressing the level of second messenger cGMP. The drop in cGMP causes closing of a Na+/Ca2+ ion channel, leading to hyperpolarization of the cell.

3. Intracellular receptors that migrate to the nucleus after binding to the ligand – here the ligand-receptor complex directly affects gene transcription. Hormone receptors are cytoplasmic proteins that bypass membrane-bound signal transduction pathways – receptors for lipophilic steroid/thyroid hormones, the glucocorticoid, vitamin D, retinoic acid and thyroid hormones. All hormone receptors are capable both of binding hormone and of directly activating gene transcription (bi-directional). After binding the hormonal ligand, the hormone-receptor complex translocates to the nucleus and binds to specific DNA sequences (hormone response elements, HREs), resulting in altered transcription rates of the associated gene.

Coupling of ligand-receptor interactions to intracellular events
1. phosphorylations by tyrosine kinases and/or serine/threonine kinases – two-component systems

Intracellular events controlled by signaling:
1. gene expression (transcription)
2. chemotaxis
3. cellular growth, proliferation, and differentiation (tyrosine and serine/threonine phosphorylation)

Protein kinases are targetted by pharmaceuticals because PKs play a variety of roles in disease states. Kinase inhibitors bind to the kinase in at least four different binding modes:
(1) direct competition with ATP at the ATP binding site;
(2) engagement of an adjacent allosteric binding site in the ATP pocket, which is usually accessible when the activation loop is in the inactive conformation; and
(3) binding at sites remote from the ATP site (but still close to the ATP) that impact kinase activity;
(4) binding outside of the ATP binding pocket (truly allosteric).

Kinases can escape inhibition by mutating key residues in their catalytic domain, thus becoming resistant to the kinase inhibitors. Those kinase that have or gain functional mutations may be more sensitive or resistant to inhibition by kinase inhibitors than is the wt form of the kinase.

▲: 7TM receptors סּ adhesion סּ cell membranes סּ chemotaxis : classes of receptors : controlled activities : coupling : DAG ~ DAG ~ DAGKs ~ diacylglycerol ~ diacyl glycerol kinase : diacylglycerol : DGKzeta : extracellular signals : GEFs : G-protein coupled receptors : guanine nucleotide-binding protein-coupled receptors : GPCR families : GPCRs סּ GPCRs סּ GPCR families s : heptahelical receptors סּ hormones: hormone receptors : HREs : intracellular signals : intracellular receptors : intercellular signals : IP3 : kinase inhibitors : ligands סּ microtubules סּ migration ₪ molecular switches סּ neurotransmission סּ neuronal interconnections : phospholipases ~ phospholipase C-gamma : phospholipids : PI3K : PKCs : protein kinases : Ras : RasGRP ¤ Ras : receptor classes סּ receptor-mediated endocytosis סּ receptor proteins : serpentine receptors ~ signaling items ¤ signaling molecules : targets for control : 7TM receptors : ▲

Chemotaxis • GPCRs • GPCR families • hormones • neurotransmission • Nitric Oxide • neuronal interconnections • phosphotransfer-mediated signaling pathways • Protein Kinase Signaling Networks • receptor tyrosine kinases •  Receptor Tyrosine Kinases (RTKs) Tables  Cell signaling  Cell Adhesion  Second Messengers  Immune Cytokines  Apoptosis vs Necrosis  Apoptosis  Malignant Transformation  Oncogenes Proto-oncogenes  Regulatory Proteins Sequences  • signaling gradients • two-component systems • animation MAPK signal transduction : more :

Signaling pathways:
Pathway ABC transporters : Pathway Phosphotransferase system (PTS) : Pathway Two-component system : Pathway MAPK signaling pathway : Pathway Wnt signaling pathway : Pathway Notch signaling pathway : Pathway Hedgehog signaling pathway : Pathway TGF-beta signaling pathway : Pathway VEGF signaling pathway : Pathway Jak-STAT signaling pathway : Pathway Calcium signaling pathway : Pathway Phosphatidylinositol signaling system : Pathway mTOR signaling pathway : Pathway Neuroactive ligand-receptor interaction : Pathway Cytokine-cytokine receptor interaction : Pathway ECM-receptor interaction : Pathway Cell adhesion molecules (CAMs) : Orthology Transporters (+diseases) : Orthology Two-component system : Orthology Receptors and channels (+diseases) : Orthology Cytokines : Orthology Cell adhesion molecules (CAMs) : Orthology CAM ligands : Orthology CD molecules : Orthology GTP-binding proteins :

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