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Cells and the Stuff They’re Made of … Lectures 3 & 4 & 5 Indiana University P575 1 Cells are the “indivisible” units of life. There is nothing smaller that is alive, nothing bigger is more alive. - J. Theriot Standard definition of life merges metabolism and replication: Metabolism: Cells consume energy from environment and use it to create ordered structures. Replication: Cells harness energy from environment to create offspring. Common ancestor several billion years ago, gave rise to three major cell types: Archaea, Bacteria, Eukaryota Lectures 3 & 4 & 5 Indiana University P575 2 Prokaryotes and Eukaryotes Prokaryotes: absence of nuclear membrane (and other organelles) Bacterium Eukaryotes: presence of nuclear membrane Fibroblast Lectures 3 & 4 & 5 Indiana University P575 3 E. coli as the Standard Ruler E. Coli is the “hydrogen atom” of cell biology. “Not everyone is mindful of it, but cell biologists have two cells of interest; the one they are studying and Escherichia coli.” – Schaechter et al. Easy to isolate Able to grow in the presence of oxygen Replicates rapidly Easy to generate mutants Lectures 3 & 4 & 5 Indiana University P575 QuickTime™ and a TIFF (LZW) decompressor are needed to see this picture. 4 Hierarchy of Spatial Scales Fly Lectures 3 & 4 & 5 Bacteriophage Compound Eyes Sperm Cell ATPaseIndiana University P575 DNA Bacterium 5 Water Molecule Some Different Cell Types Referenced to E. coli as the standard ruler QuickTime™ and a TIFF (LZW) decompressor are needed to see this picture. Lectures 3 & 4 & 5 Indiana University P575 A: Giardia lamblia B: Plant cell C: S. cerevisiae D: Red blood cell E: Fibroblast cell F: Nerve cell G: Rod cell 6 Cellular Interior: Organelles Red: Nucleus Yellow: Golgi Green: Microtubules Lectures 3 & 4 & 5 Indiana University P575 7 Information Processing and Storage: Nucleus Lectures 3 & 4 & 5 Indiana University P575 8 Energy Production: Mitochondria Lectures 3 & 4 & 5 Indiana University P575 9 Lipid and Protein Production: Endoplasmic Reticulum Lectures 3 & 4 & 5 Indiana University P575 10 Lipid/Protein Processing and Trafficking: Golgi Appartus Lectures 3 & 4 & 5 Indiana University P575 11 How do we know about cellular and subcellular structures? Common techniques: (A) fluorescence microscopy (B) atomic force microscopy (C) electron microscopy Lectures 3 & 4 & 5 QuickTime™ and a TIFF (LZW) decompressor are needed to see this picture. Indiana University P575 12 Cellular Interiors: Molecular Parts Proteins, Nucleic Acids, Lipids, Carbohydrates: Each class can be assembled by the cell from a small number of simpler subunits or precursor molecules A cell needs only a restricted repertoire of biochemical reactions to synthesize the subunits from food in the environment Combinatorial assembly of subunits gives rise to huge structural diversity making up the stuff of cells QuickTime™ and a TIFF (LZW) decompressor are needed to see this picture. A: DNA (nucleic acid) B: Hemoglobin (protein) C: Phosphatidylcholine (lipid) D: Branched carbohydrate Lectures 3 & 4 & 5 Indiana University P575 13 Examples of Molecular Types Glucose Galactose QuickTime™ and a TIFF (LZW) decompressor are needed to see this picture. QuickTime™ and a TIFF (LZW) decompressor are needed to see this picture. QuickTime™ and a TIFF (LZW) decompressor are needed to see this picture. Lectures 3 & 4 & 5 DNA Hemoglobin Indiana University P575 Phosphatidylcholine 14 Two “Great Polymer Languages” Alphabet: Nucleotides (4) Amino Acids (20) Words: Codon (3 nucleotides) Elements of secondary structure Sentences: Genes (~4500 in E. coli) Fully folded proteins Lectures 3 & 4 & 5 Indiana University P575 15 Macromolecular Assemblies (by shape) Helical protein assemblies are ubiquitous. QuickTime™ and a TIFF (LZW) decompressor are needed to see this picture. Lectures 3 & 4 & 5 Indiana University P575 16 Macromolecular Assemblies (by function) Proteins, nucleic acids, lipids, sugars acting as a team (“-somes”): ~10 nm scale Lectures 3 & 4 & 5 Indiana University P575 QuickTime™ and a TIFF (LZW) decompressor are needed to see this picture. 17 Macromolecular Superstructures QuickTime™ and a TIFF (LZW) decompressor are needed to see this picture. (A) Ribosomes on ER (B) Myosin filaments in myofibrils in muscle cells (C) Microvilli at epithelial surface Lectures 3 & 4 & 5 Indiana University P575 18 Molecular Representation Atomic level structure revealed through: X-ray crystallography Nuclear magnetic resonance (NMR) Cryo-electron microscopy Leading to: QuickTime™ and a TIFF (LZW) decompressor are needed to see this picture. (A) Ball-and-stick (B) Space-filling (C) Ribbon diagrams. Eg. Triose phosphate isomerase: Enzyme involved in glycolysis pathway Lectures 3 & 4 & 5 Indiana University P575 19 Molecular Composition of (Bacterial) Cell Molecular Class % of total cell weight Small Molecules ions, inorganic molecules sugars fatty acids individual amino acids individual nucleotides water (74%) 1.2 1 1 0.4 0.4 70 Medium and Big Molecules protein DNA RNA lipids polysaccharides (26%) 15 6 1 2 2 (From Alberts, et al., MBoC) Lectures 3 & 4 & 5 Indiana University P575 20 Fantastic Voyage … Movie available at: See also D. Liu, “Seeing Cells on the Web”: http://www.lifescied.org/cgi/content/full/6/1/21 Lectures 3 & 4 & 5 Indiana University P575 21 Science is built up of facts, as a house is with stones. But a collection of facts is no more a science than a heap of stones is a house. - Henri Poincare Lectures 3 & 4 & 5 Indiana University P575 22 Molecular Census Why do we care about numbers of different molecules inside the cell? Quantitative understanding of cellular phenomena requires quantitative knowledge of the numbers of key players (molecules) involved and the spatial dimensions over which they act. Molecular counts will determine rates of macromolecular synthesis during the cell cycle (genome replication, protein synthesis rates). Small or large molecular copy numbers determine the qualitative nature of chemical reactions (stochastic vs deterministic). Lectures 3 & 4 & 5 Indiana University P575 23 Sizing up E. coli Estimate: Nprotein, Nribosome, Nlipid, NH20, Nion !! … back to the chalkboard. Conclusion: The cell is a very crowded place! Lectures 3 & 4 & 5 Indiana University P575 24 Recap … Hierarchy of Spatial Scales Hierarchy of spatial scales: Atom DNA Organelles Virus Bacterial Cell Eukaryotic Cell Multicellular Aggregates Tissue Organism Lectures 3 & 4 & 5 Indiana University P575 Quick Time™ and a TIFF (LZW) dec ompressor are needed to s ee this pic ture. 25 Spatial Organization at the Cellular Level Organelles (nucleus, ER, Golgi apparatus, lysosome …) Macromolecular superstructures (myofibrils, microvilli …) Macromolecular complexes (ATPase, replisome, proteosome…) Proteins, nucleic acids, carbohydrates, lipids (enzymes, DNA/RNA, polysaccharides, phospholipids…) Amino acids, nucleotides, small sugars, fatty acids Inorganic molecules, water, ions (How is this organization achieved? Expenditure of energy!) Lectures 3 & 4 & 5 Indiana University P575 26 Hierarchy of Biologically Relevant Time Scales Dynamics on scales of: Molecules Biochemical reactions Cells Organisms Evolution QuickTime™ and a TIFF (LZW) decompressor are needed to see this picture. ranging from femtoseconds to billions of years! Lectures 3 & 4 & 5 Indiana University P575 27 E. coli as the standard clock Organismal and cellular time scales Lectures 3 & 4 & 5 Indiana University P575 QuickTime™ and a TIFF (LZW) decompressor are needed to see this picture. 28 E. coli as the standard clock, cont’d Subcellular time scales Lectures 3 & 4 & 5 Indiana University P575 QuickTime™ and a TIFF (LZW) decompressor are needed to see this picture. 29 Central Dogma of Molecular Biology DNA (template for DNA, RNA) RNA (mRNA: template for proteins) QuickTime™ and a TIFF (LZW) decompressor are needed to see this picture. Protein Biochemical networks (computing language of cell) Timing the machines of the central dogma: Homework! Lectures 3 & 4 & 5 Indiana University P575 30 Amendments! Some examples… Cell’s heritable characteristics are not solely determined by DNA; rather, a cell’s entire state (protein content) determines fate of descendants (eg. differentiation, transmission of pathology through prions,…) RNA editing between mRNA synthesis and translation Post-translational modification; chaperones and proteases Lectures 3 & 4 & 5 Indiana University P575 31 DNA/RNA Building Blocks DNA/RNA are nucleic acids consisting of nucleotides (base+sugar+phosphate) subunits. DNA: deoxyribose (sugar) ATGC (bases) Lectures 3 & 4 & 5 Indiana University P575 RNA: ribose (sugar) AUGC (bases) 32 DNA Assembly covalent bonding Lectures 3 & 4 & 5 hydrogen bonding Indiana University P575 33 3D Structure DNA RNA Base pairing yields double helix in DNA Single helix and variety of folded structures in RNA Discovery of DNA structure and function through combined efforts of chemists (Franklin), biologists (Watson and Wilkins) and physicists (Crick)! Lectures 3 & 4 & 5 Indiana University P575 34