fcp-1: cell biology
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FCP-1: Cell Biology
1st contact session: cell membranes, cytoplasmic organelles, the cytoskeleton, intercellular
connections, cell adhesion molecules, transport across cell membranes, ATP production
Part 1: intracellular structures and organelles
Simplified depiction of a cell
Cell membrane components
• Main component: phospholipids (hydrophilic outside, hydrophobic inside, spontaneous bi-layer)• Selectively permeable• Inner membranes have similar structure• Proteins: integral vs peripheral• Modifications• Anchors
Cell adhesion molecules, pumps, channels, receptors, enzymes
Mitochondria (1)
Main function: energy production throughoxidative phosphorylation
Mitochondria (2)
• Used to be free-living bacteria• Contains the components of the electron transport chain
(energy production) in the inner membrane• Contains own genome (smaller than nucleus) and
ribosomes (protein synthesis machinery)• Zygote mitochondria come from the ovum: maternal
inheritance of mtDNA• Very ineffective DNA repair leads to mistakes: results in
a large number of rare diseases associated with defects in energy metabolism
Mitochondria (3)Electron transport chain (oxidative phosphorylation, generation of ATP/energy):
Later…
Lysosomes: rubbish bins
• Large, irregular structures in the cytoplasm• Acidic interior, digest endocytosed bacteria and
discarded cell components• Filled with acid hydrolases, cannot function at normal
cellular pH, will not destroy other cell components• Lysosomal storage diseases result from absence of
enzyme, accumulation/engorgement of lysosomes
Peroxisomes: detox and more • Catalyse various anabolic and catabolic reactions, e.g.
breakdown of very long chain fatty acids, production of plasmalogen (myelin), production of bile acids
• Enzymes oxidize substrates, generating toxic H2O2, used to oxidize other substrates, neutralizing H2O2
• NB for the detox of ethanol• PXR gene product is outer pxome receptor, PEX gene
products import proteins into pxome, and enzymes are targeted into pxome by PTS signal
• Errors in pxome assembly result in Zellweger syndrome, neonatal adrenoleukodystrophy and infantile Refsum disease (lethal in infants)
Nucleus: command HQ
• Contains all of the DNA (nuclear genome) required for gene expression, in the form of chromatin• Site of gene expression (DNA → mRNA)
Nucleus
• DNA (chromosomes) normally unravelled, disorganized: chromatin
• Individual chromosomes condense before cell division• Nucleolus contains RNA, proteins:
ribosome assembly• Nuclear envelope a double-layer membrane• Contains pore complexes for shuttling of
proteins, ribosomes and RNA: ribosomes and RNA produced in nucleus, must shuttle to cytoplasm for protein synthesis, some proteins (i.e. transcription factors) must shuttle back to nucleus
Ribosomes: protein assembly lines
Endoplasmic reticulum: processing
• Complex series of tubules in the cytoplasm• Contiguous to the nuclear membrane• Smooth ER: steroid synthesis • Rough ER: covered with ribosomes,
protein synthesis, folding and
modification
Golgi apparatus: add some sugar
• Stacked membrane-enclosed sacs• Proper glycosylation (sticking on carbohydrate/sugar
chains) of lipids and proteins• Directional (cis→trans)• Vesicles shuttle from the ER, through the Golgi, out for
secretion
Cytoskeleton: intracellular highways
• Maintains structure, helps to move and change shape• Also moves proteins and organelles around
Molecular motors to move cargo
Kinesin, dynein, myosin: all use ATP (energy)
Part 2: Intercellular connections
Holding cells together: Tight junctions
• Surround the outer layer of epithelial cells (intestinal mucosa, renal tubules, choroid plexus in brain)• Also contribute to endothelial barrier function• Totally obliterates the gap between cells, prevents protein leakage between cells
Holding cells together: zonula adherens
Holding cells together: desmosomes
- Adhesion protein = cadherin, helps to withstand shear stress in epithelium, particularly in epidermis- Defining feature: dense plaques on cytoplasmic side, attached to cytoskeletal filaments- Blistering diseases (Pemphigus) are auto-immune, attack desmogleins(cadherins), cause layers of skin to pull apart
Attaching cells to the basal lamina: hemidesmosomes and
focal adhesions
Gap junctions: intercellular communication
• 1 subunit = connexin• Pore with 6 connexins = connexon• permit passage of ions and small metabolites between cells• highly selective (20 diff connexin genes, each for different flow-through)
Cell adhesion molecules
• All intercellular connections consist of cell adhesion molecules (CAMs)
• 4 broad families: integrins, cadherins, selectins and IgG adhesion molecules
• Not just for adhesion, but also for signalling:• cells that lose contact with other cells undergo dissociation-induced apoptosis (anoikis)• collagen-integrin interaction essential for osteoblast differentiation
Part 3: transport across cell membranes
Exo- and endocytosis
Note that the cytoplasmic side of the membrane always remains the cytoplasmic side
Endocytosis continued
• Phagocytosis: eating of bacteria, dead tissue by leukocytes
• Pinocytosis: drinking of solutes• Both processes involve invagination of the plasma
membrane before pinching off vesicle inside the cell• Clathrin-mediated endocytosis: three-legged clathrin
molecules cover endocytotic vesicle
(NB for receptor internalization and
synaptic function)
How do molecules move across the cell membrane?
• Small non-polar and neutral polar molecules diffuse directly across (O2, N2 CO2)
• Everything else needs help!• Transport proteins form channels for transport of various
molecules• Even water! (through aquaporins)• Some are non-selective ion
channels, some are very selective
How do molecules move across the cell membrane?
• Some channels are gated
(opened upon a particular
stimulus):
How do molecules move across the cell membrane?
• Carrier proteins transport molecules WITH a concentration or electrical gradient: facilitated diffusion, does not require energy (example: glucose)
• Other carriers transport molecules AGAINST a gradient: active transport, requires energy
• Many carrier proteins are therefore ATPases: hydrolyses ATP for energy for transport
• Secondary active transport: transport of one molecule coupled to the transport of another (often Na+)– Symport: two molecules moving in the same direction– Antiport: exchange of molecules in opposite directions
Ion channels
Possible configurations:
Part 4: Energy (ATP) production
ATP hydrolysis = energy
ATP → ADP + Pi + 30-50 kJ energy
Energetically unfavourable (unstable) Energetically more stable
Interesting factoid: 60% of energy goes towards maintenance of body temp
Main site of ATP production: the citric acid cycle
cytoplasm
mitochondria
But before we get to this point…..
Glycolysis (Embden-Meyerhof pathway)
1x 6-carbon
2x 3-carbon
Net gain (1 mol glucose): 4 ATP – 2 ATP = 2 ATP; 2 pyruvate; 2 NADH
Or….Glycogen breakdown
Net gain from 1 mol glucose-6-phosphate: 4 ATP – 1 ATP = 3 ATP; 2 pyruvate; 2 NADH
Or…Beta-oxidation of fatty acids
- Takes place in mitochondria: long-chain fatty acids transported in by carnitine- 18-C fatty acid generates 8 acetyl-CoA
Main site of ATP production: the citric acid cycle
cytoplasm
mitochondria
From NADH/FADH2 to ATP
ATP production: adding it up
• 1 pyruvate generates 4 NADH, 1 FADH2 and 1 GTP (ATP)
• 1 NADH = 3 ATP, 1 FADH2 = 2 ATP
• 1 pyruvate = (4x3) + (1x2) + 1 = 15 ATP• 1 glucose (2 ATP; 2 pyruvate; 2 NADH) = 2 +
(2x15) + (2x3) = 38 ATP• 1 glucose-6-P (from glycogen) = 39 ATP• 1 18-C fatty acid = 8 x 15 = 120 ATP• 1 triglyceride ≥ 360 ATP
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