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Protein Synthesis DNA at work If DNA = recipe book Proteins = courses of a meal • Recipes for all polypeptides are encoded by DNA • mRNA is a copy of that recipe (DNA sequence) • mRNA (recipes) travel to ribosomes for translation into polypeptides (proteins) Early developments • 1909: A. Garrod suggests that “genes” create phenotypes via enzymes – Genes: heritable units of DNA – Phenotype: observable characteristic – People who lack particular enzymes have disease phenotypes (metabolic incompetence) Early developments • 1940’s: Beadle & Tatum; Neurospora crassa (mold) produce thousands of offspring; some cannot grow on traditional food source = nutritional mutants – Could these mutants lack an enzyme? Early developments • They do! • It’s often one dysfunctional enzyme per mutant, and one dysfunctional gene • One gene-one enzyme hypothesis – One gene-one protein • One protein-one polypeptide Protein recipe is written in genetic code (genes) • Genes lie along DNA – What are chromosomes? • Genes are linear sequences of nucleotides • One, three-nucleotide sequence = codon Genetic code & codons • Each codon codes for a particular Amino Acid • Each gene has many codons in it • Codons also exist for “start translating” and “stop translating” Genetic code & codons • Redundant – multiple codons specify same AA • Unambiguous - NO codon specifies more than one AA • Ancient – ALL organisms have same genetic code – AUG = Methionine whether you’re a redwood or a fruitfly How RNA is made • • RNA polymerase adds RNA nucleotides to DNA template RNA molecule peels away from DNA strand How RNA is made 1. Initiation: RNA polymerase binds to a promoter (specific nucleotide sequence) 2. Elongation: Polymerase adds complementary nucleotides to DNA template; RNA peels away, DNA reconnects How RNA is made 3. Termination: RNA polymerase reaches “terminator sequence”. 3. RNA polymerase detaches; mRNA detaches Further processing • Addition of caps (G) & tails (poly A) by RNA polymerase – Allow recognition by ribosomes (Cap, Tail) – Protect RNA from RNase attack (Cap) – Protect RNA from exonuclease attack (Tail) – Allow export by transporter molecules Further processing • Introns spliced out – Intervening sequences; NOT transcribed into polypeptide • Exons joined – Coding regions of DNA that are transcribed into Amino Acids tRNA brings appropriate AA • tRNA is “cook’s helper” – Brings individual ingredients (AA) to make the recipe (protein) • Binds appropriate AA (in cytoplasm) • Recognizes the mRNA codon that specifies its AA – Complementary nucleotide sequence (Anticodon) for recognition tRNA binding sites • Anticodons & AA attachment sites are themselves a string of three nucleotides • One enzyme attaches each AA to any of its possible tRNA transporters Ribosomes & Translation • rRNA plus proteins – 2 rRNA subunits • Bind mRNA • Bind tRNA with attached Amino Acids Ribosomes • Small subunit binds mRNA • Large subunit, with tRNA binding sites, attaches to small subunit + mRNA 1. Initiation • • Translation mRNA binds to small subunit. Initiator tRNA binds to start codon, always AUG -> first AA of all polypeptides is always Met 2. Elongation • • Translation* Large subunit binds to small -> functional ribosome Initiator tRNA attaches to P site of ribosome. Holds growing polypeptide. Next tRNA attaches to A site Translation 2. Elongation 1. Codon recognition: tRNA anticodon binds to mRNA codon in the A site 2. Peptide bond formation: Polypeptide detaches from tRNA in P site & binds to AA & tRNA in A site Translation 2. Elongation 3. Translocation: tRNA in P site detaches, A site tRNA & mRNA move, as unit, into P site. New tRNA attaches to A site. 3. Termination – Stop codon is reached; no AA is added; polypeptide releases & subunits dissociate DNA – RNA - Protein • Gene expression Mutations • Any change in nucleotide sequence – Substitutions – Insertions – Deletions • Many alternative phenotypes result from single nucleotide changes Point Mutations • Substitution: – A single base pair is changed. – Synonymous (silent): results in NO AA change…why not? – Nonsynonymous: results in single AA change – These are less likely to be deleterious. WHY? Example* • Hemoglobin mutations – HbE: Codon position 26; Replace GLU w/ LYS; reduced Hb production. Hemoglobin instability at low O2 – HbC: Position 6; Replace GLU w/ LYS; RBC’s become rigid & crystalize – HbS: Position 6; Replace GLU w/ VAL; At low O2, Hb polymerizes & RBC’s collapse Point Mutations • Indels: insertions/ deletions – A single nucleotide is inserted or deleted – Far more likely to be deleterious because these shift the reading frame (triplet grouping) Sources of mutation* • Mutagenesis: Production of mutations • Spontaneous mutations: – Errors in replication coupled with subsequent errors in proofreading – Errors in chromosome (DNA) separation during cell division • Mutagens: Physical or chemical agents – X-rays, UV light (high energy photons)