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Similaire à Basic biology of nerves: Protein synthesis and transport
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Basic biology of nerves: Protein synthesis and transport
- 1. Basic biology of nerves proteins: synthesis and movement DR SERGE EDDY MBA
- 2. Historical background oAugustus Waller (1850) oNeuron doctrine 19th CE ….His(embryonal studies) Forel (response to injury) Cajal(histological observations) oElectron microscope (1950) : demonstrate lack of cytoplasmic continuity between neurons
- 3. ANATOMY OF A NEURON
- 4. Anatomy of a nerve cell oDentrides: branche projections oCell body: Soma, perikaryon, cyton oAxons: Greek axis, oBoutons terminaux
- 5. NEURONAL PROTEINS “A nerve-cell would be to its effluent nerve fibers what a fountain is to the rivulet which trickles from it—a centre of nutritive energy.” Waller (1861) The brain expresses more of the total genetic information encoded in DNA than does any other cell in the body In mature neurons, the chromosomes no longer duplicate and therefore function only in gene expression Ribosomal RNA is transcribed in the nucleoli Precursor RNA is transcribed in the nucleus to generate mRNA Newly synthesized ribosomes and mRNA are exported from the nucleus through nuclear pores The synthesis of all protein starts in the CYTOSOL
- 6. Initiation elongation termination TRANSLATION The final destination of the newly synthesized protein is encoded into its AA sequence
- 7. Free polysomes RER Secretory proteins cytosolic Actively imported
- 8. Functionality of proteins Determined by amino acid sequence Correct folding of polypeptide chain (secondary and tertiary structure) Folding may occur spontaneously or can be catalyzed by interactions with chaperones (e.g.HSP) Cotranslational post translational N-acylation Thioacylation Isoprenylation Phosphorylation Glycosylation Ubiquination
- 9. N - ACYLATION o Transfer of an acyl group to the N terminus of the growing polypeptide chain oAcylation can occur by a Myristoyl group (carbon saturated fatty acid) oThis allows the modified protein to associate with membrane through the lipid chain oExamples of N-myristoylated proteins include: oThe catalytic subunit of cAMP-dependent protein kinase oCalcineurin
- 10. THIOACYLATION oAnchors proteins to the cytosolic leaflet membranes oIt occurs i.e in t-SNARE and SNAP25 (fusion) oGrowth Associated Protein (GAP-43) also called Neuromodulinis another protein that has been thioacylated oHumans with a deletion in one allele of the GAP43 gene fail to form telencephalic commissures and are mentally retarded
- 11. ISOPRENYLATION oPost translational modification oImportant in anchoring proteins to cytosolic membranes oHappens shortly after synthesis and involves a series of steps o thioacylation with farnesyl or with geranyl-geranyl oFarnesylation and geranylation have important roles in vesicle transport reactions oprogeria
- 12. PHOSPHORYLATION oReversible post translational modification … oMost common mechanism for altering physiological processes oCatalysed by protein phosphatases oExamples of these reactions include oPhosphorylation/dephosphorylation that regulate the kinetics of ion channels , activity of transcription factors, the assembly of cytoskeleton, the activity of enzymes…
- 13. GLYCOSYLATION oOccurs on the amino groups of Asparagine residues (N-linked glycosylation) oResults in addition of complex polysaccharide chain oCell to cell interaction that occur during development rely on molecular recognition between glycoproteins oGlycosylation increases the repertoire configurations a protein can have oGlycosylation helps anchor several proteins to the outer leaflet of the plasmalemma including a form of Acetylcholinesterase and NCAM (Neuronal Cell Adhesion Molecule)
- 14. UBIQUITINATION oUbiquitin is a highly conserved protein with 76 aa oAttaches to the ɛ-amino group of Lysine residues within the protein molecule oTags the protein for degradation oATP-ubiquitin-proteasome pathway is present in ALL regions of the neuron oNot only for denatured/old protein degradation but also SYNAPTOGENESIS and LT MEMORY
- 15. Synthesis of transmembrane proteins
- 17. Some of the proteins synthesized in the endoplasmic reticulum remain in this organelle as resident proteins. Others are targeted to other compartments of the vacuolar apparatus, to the plasmalemma, or to the extracellular space by secretion. Proteins within the lumen of the endoplasmic reticulum are extensively modified Disulfide linkages are crucial to the tertiary structure of proteins within the ER lumen
- 18. Synthesis of secretory proteins
- 19. THE GOLGI COMPLEX oAppears as stack of flattened cisternae aligned with one another in ribbons oEach subcompartment is specialized for different types of enzymatic reactions oSeveral protein modifications occur aiming at increasing the hydrophilicity of the protein ( fine tuning their ability to bind other molecules and delaying their degradation.
- 21. PROTEIN TRAFFICKING oMembranous organelles move in an anterograde or retrograde direction by fast axonal transport (400mm/day) oThese organelles include: synaptic vesicles precursors, mitochondria, elements of SER oCytosolic and cytoskeletal proteins move only in the anterograde direction by slow axonal transport oParticles are transported in a salutatory fashion along linear tracts aligned with the main axis: Microtubules
- 22. ANTEROGRADE TRANSPORT o Is dependent on ATP o Is not affected by inhibitors of protein synthesis o Does not depend on the cell body o depends on microtubules that provide stationary tract on which specific organelles move by means of molecular motors o salutatory movement is due to periodic dissociation of the organelles from the tract and to collision with other organelles o motor molecules for anterograde transport are KINESINS and a variety of kinesin related proteins called KIF o slow axonal transport only occurs in the anterograde direction
- 23. RETROGRADE TRANSPORT oThe rate of retrograde fast transport is about one-half to two-thirds that of fast transport in the anterograde direction. o particles move along microtubules. oThe motor molecule for retrograde transport is a microtubule-associated ATPase called MAP-1C. oRetrograde transport is used to deliver signals to the cell body e.g activated growth factor oreceptors are thought to be carried along the axon to their site of action in the nucleus. o Certain toxins (tetanus toxin) as well as pathogens (herpes simplex, rabies, and polio viruses) are also transported toward the cell body along the axon. oThe faster component of slow axonal transport is about twice as fast as the slower component.
- 24. references oYoung SG, Yang SH, Davies BS, Jung HJ, Fong LG (2013). "Targeting Protein Prenylation in Progeria". Sci Transl Med 2 (5): 171. doi:10.1126/scitranslmed.3005229. oBarr’s, THE HUMAN NERVOUS SYSTEM: AN ANATOMICAL VIEW POINT, 10TH Ed oEric R.Kandel, PRINCIPLES OF NEURAL SCIENCE, 4th Ed oBates S; Vousden KH (February 1996). "p53 in signaling checkpoint arrest or apoptosis". Curr. Opin. Genet. Dev. 6 (1): 12–8. doi:10.1016/S0959-437X(96)90004-0. PMID 8791489 ohttp://www.uniprot.org/uniprot/P17677
Notes de l'éditeur
- Augustus Waller: He created the first practical ECG machine with surface electrodes conducted experiments on frogs, cuts a nerve an observe His: neuron is the functional unit of the nervous system.
- Nerve cells have four distinctive compartments: dendrites, for receiving signals from other neurons; the cell body, which contains the DNA encoding neuronal proteins and the complex apparatus for synthesizing them; the axon, which projects over long distances to target cells (for example, other neurons or muscle); and nerve terminals, for release of neurotransmitters at synapses with targets
- Dendrites (from Greek déndron, "tree")(also dendron) are the branched projections of a neuron that act to propagate the electrochemical stimulation received from other neural cells to the cell body, or soma, of the neuron from which the dendrites project The soma (pl. somata or somas), perikaryon (pl. perikarya), cyton, or "cell body" is the bulbous end of a neuron, containing the cell nucleus. The word "soma" comes from the Greek σῶμα, meaning "body An axon (from Greek , axis), also known as a nerve fibre, is a long, slender projection of a nerve cell, or neuron, that typically conducts electrical impulses away from the neuron's cell body
- About 20.000 distinct mRNA are thought to be expressed, that is 20 times more than the liver This is because of the greater variety of cell types in the brain
- Translation of mRNA start from the 5’ end which encodes the N-terminal end of the protein The proseess then progresses codon by codon until a desired protein molecule is finished
- Majority of newly synthesized proteins remain in the cytosol (fibrillar elements that make up the cytoskeleton and numerous enzymes that catalyse metabolic reaction in the cell Actively imported 1.into the nucleus 2.the peroxisomes 3.the mitochondria Only secretory proteins and proteins of the vacuolar apparatus and plasmalemma are synthesized and modified in the endoplasmic reticulum.
- Chaperones are Proteins that bind to unstructured exposed regions of the newly synthesized polypeptide An example of a chaperone is the Heat Shock Protein HPS70 and HPS60 Catalysed because it is energy dependent
- About 80% of cell’s proteins are acylated Calcineurin is a major calcium dependant protein phosphatase that activate T-cell in the immune system Calcineurin is linked to receptors for several brain chemicals including NMDA, dopamine and GABA.[5] An experiment with genetically-altered mice that could not produce calcineurin showed similar symptoms as in humans with schizophrenia: impairment in working memory, attention deficits, aberrant social behavior, and several other abnormalities characteristic of schizophreni
- T-SNARE and SNAP are proteins that facilitate the fusion of vesicles with the plasma membranes GAP-43 binds both actin and calmodulin This protein is associated with nerve growth. It is a major component of the motile "growth cones" that form the tips of elongating axons
- A 2012 clinical trial explored the approach of inhibiting protein prenylation with some degree of success in the treatment of Hutchinson-Gilford progeria syndrome, a multisystem disorder which causes failure to thrive and accelerated atherosclerosis leading to early death
- Phosphorylation of Na+/K+-ATPase during the transport of sodium (Na+) and potassium (K+) ions across the cell membrane in osmoregulation to maintain homeostasis of the body's water content
- The generation of transport vesicles from a membrane is assisted by protein coats, which assemble at the cytosolic surface of the membrane patches that will form the vesicles. These coats are thought to have two functions. First, they mediate evagination of the membrane into a bud. Second, they select the protein cargo that will be incorporated into the vesicles. There are several types of coats. The clathrin coat assists in budding from the Golgi complex and from the plasmalemma. Two other coats, COPI and COPII, assist the vesicles involved in transport between the endoplasmic reticulum and the Golgi complex. The coats are rapidly lost once free vesicles have formed. Docking and fusion of vesicles with the target membrane is mediated by a hierarchy of molecular interactions, the most important of which is thought to be the reciprocal recognition of small proteins with short membrane anchors on the cytosolic surfaces of the two interacting membranes. The action of these small proteins, called v-SNARE (vesicular SNARE) and t-SNARE (target membrane SNARE), is discussed in connection with the role of synaptic vesicles in the release of neurotransmitter at synapses.
- An important question that remains is how the proteins that form synaptic vesicles reach axon terminals? This little ka diagram is some form of an answer. Keep your eyes riveted to the blue kinesin…we will get to know more about it later.
- 2500 days to cover one kilometer
- Analogy with saltatory conduction