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2.4: Central Dogma and the Genetic Code

  • Page ID
    18129
  • The "Central Dogma"

    We have seen how DNA, with the aid of specific polymerases and accessory proteins, is able to replicate. We have also seen how we can use this information to create autonomously replicating extra-chromosomal elements (i.e. plasmids). However, the real utility of such systems arises when we use them to create proteins of interest. To get to proteins we have to go through RNA first.

    Screenshot (252).png

    Figure 2.4.1: Central dogma

    Structural features of RNA:

    1. Similar to DNA except it contains a 2' hydoxyl group (makes phosphodiester bond more labile than DNA).
    2. Thymine in DNA is replaced by Uracil in RNA

    Screenshot (253).png

    Figure 2.4.2: Thymine vs. Uracil

    3. RNA's can adopt regular three-dimensional structures which allow them to function in the process of genetic expression (i.e. the production of proteins).

    • This ability to adopt defined three dimensional structures which impart functionality places RNA in a unique class - somewhat akin to proteins, and different from DNA.
    • For example certain RNA molecules, when folded, exhibit catalytic capacities (e.g. the cleavage of RNA molecules).
    • The majority of RNA in cells is found in complexes with proteins. The most common example is ribosomes (involved in protein synthesis).

    Transcription: the copying of DNA by an RNA polymerase to make RNA.

    RNA polymerase:

    • Can initiate a new nucleic acid strand given a template.
    • DNA polymerases cannot; they require a primer (or more typically, an RNA polymerase to provide the primer).

    Protein Synthesis

    • Three kinds of RNA molecules perform different functions in the protein synthesizing apparatus:
    1. Messenger RNA (mRNA) encodes the genetic information copied from DNA in the form of a sequence of bases that specifices a sequence of amino acids
    2. Transfer RNA (tRNA) is part of the structural machinery which deciphers the mRNA code. They carry specific amino acids which are transfered to a nacent polypeptide according to the instructions contained within the mRNA.
    3. Ribosomal RNA (rRNA) forms a complex with specific proteins to form the ribosome which is the key translational component
      • the ribosome complexes with mRNA and directs appropriate tRNA's and the synthesis of the polypeptide bond.

    Translation:

    The process by which the information contained within a mRNA is used to direct the synthesis of the corresponding polypeptide.

    The Genetic Code

    How is the information for a polypeptide sequence stored within an mRNA molecule? There are twenty different common amino acids, but only four different bases in RNA (A, C, G, and U).

    Base Arrangement

    Possible Combinations

    1

    41=4

    2

    42=16

    3

    43=64

    4

    44=256

    A triplet arrangement would seem to be the minimum possible combination necessary to code for the 20 different amino acids. Although, there are obviously going to be a lot of codons "left over". Most amino acids are coded for by more than a single unique triplet, and therefore the genetic code is said to be degenerate.

    Experiments which led to the solution of the genetic code:

    Nirenberg and Matthei (1961): Nirenberg and Matthei worked with bacterial extracts which contained everything needed for translation, with the exception of mRNA. To this they added either poly A, poly U or poly C RNA. The proteins produced by the translation of these RNA's was determined (poly G did not work, probably due to conformational problems):

    Poly U

    Poly A

    Poly C

    Phe

    Lys

    Pro

    Thus, the triplet UUU = Phe, AAA = Lys, and CCC = Pro.

    Korana (1963): In a cell free extract system, Korana added mRNA with repeating nucleotide sequences. The sequence ...ACACACAC... resulted in a polypeptide with alternating threonine and histidine residues. But, was threonine coded by ACA, and histidine by CAC? Or vise versa? To determine the answer to this, the mRNA sequence ...AACAACAACAAC... was tried. There were three different possible reading frames for the translation of this mRNA:

    • AAC AAC AAC
    • ACA ACA ACA
    • CAA CAA CAA

    But CAC was not a possible triplet. This sequence was found to code for three different polypeptide chains: poly Asn, poly Thr, and poly Gln. Since no histidine was found, histidine was therefore coded for by the triplet CAC.

    Nirenberg and Leder (1964): Nirenberg and Leder used a filter which would allow RNA triplets and charged tRNA's to pass through, but would prevent passage of larger ribosomes. Specific triplet RNA sequences would bind to ribosomes and cause the binding of the associated charged tRNA molecules (coded for by the specific triplet). In a given experiment, if a unique charged tRNA were radiolabeled (on the amino acid), then it could be determined whether that particular charged tRNA was associated for by the unique triplet. In this way, all 61 codons for amino acids were determined.

    Screenshot (254).png

    Figure 2.4.3: Nirenberg and Leder experiment

    The genetic code

    5' End (Start)

    Second Position

    3' End

    U

    C

    A

    G

    U

    Phe
    0.24

    Ser
    0.34

    Tyr
    0.25

    Cys
    0.49

    U

    Phe
    0.76

    Ser
    0.37

    Tyr
    0.75

    Cys
    0.51

    C

    Leu
    0.02

    Ser
    0.02

    Stop

    Stop

    A

    Leu
    0.03

    Ser
    0.04

    Stop

    Trp
    1.00

    G

    C

    Leu
    0.04

    Pro
    0.08

    His
    0.17

    Arg
    0.74

    U

    Leu
    0.07

    Pro
    0.00

    His
    0.83

    Arg
    0.25

    C

    Leu
    0.00

    Pro
    0.15

    Gln
    0.14

    Arg
    0.01

    A

    Leu
    0.83

    Pro
    0.77

    Gln
    0.86

    Arg
    0.00

    G

    A

    Ile
    0.17

    Thr
    0.35

    Asn
    0.06

    Ser
    0.03

    U

    Ile
    0.83

    Thr
    0.55

    Asn
    0.94

    Ser
    0.20

    C

    Ile
    0.00

    Thr
    0.04

    Lys
    0.74

    Arg
    0.00

    A

    Met (start)
    1.00

    Thr
    0.07

    Lys
    0.26

    Arg
    0.00

    G

    G

    Val
    0.51

    Ala
    0.35

    Asp
    0.33

    Gly
    0.59

    U

    Val
    0.07

    Ala
    0.10

    Asp
    0.67

    Gly
    0.38

    C

    Val
    0.26

    Ala
    0.28

    Glu
    0.78

    Gly
    0.00

    A

    Val
    0.16

    Ala
    0.26

    Glu
    0.22

    Gly
    0.02

    G

    Note

    E. coli codon preferences are indicated.

    All proteins in prokaryotes and eukaryotes begin translation with the initiator codon AUG (methionine). The three codons, UAA, UGA and UAG are termination codons (don't code for any amino acids but signal the end of the protein chain).

    Note the apparent relative importance of the middle base in the codon triplet

    Middle base in codon triplet

    U

    C

    A

    G

    Phe

    Leu

    Ile

    Met

    Val

    Ser

    Pro

    Thr

    Ala

    Tyr

    His

    Gln

    Asn

    Lys

    Asp

    Glu

    Stop

    Cys

    Trp

    Arg

    Ser

    Gly

    Stop

    Hydrophobic

    Small/Polar

    Charged/Polar

    Polar

    Can common protein architectures be patterned by a simple quaternary pattern of residues?

    The twenty common amino acids and their three-letter and single-letter acronyms:

    Amino Acid

    Three letter acronym

    One letter acronym

    Alanine

    Ala

    A

    Cysteine

    Cys

    C

    Aspartic Acid

    Asp

    D

    Glutamic Acid

    Glu

    E

    Phenylalanine

    Phe

    F

    Glycine

    Gly

    G

    Histidine

    His

    H

    Isoleucine

    Ile

    I

    Lysine

    Lys

    K

    Leucine

    Leu

    L

    Methionine

    Met

    M

    Asparagine

    Asn

    N

    Proline

    Pro

    P

    Glutamine

    Gln

    Q

    Arginine

    Arg

    R

    Serine

    Ser

    S

    Threonine

    Thr

    T

    Valine

    Val

    V

    Tryptophan

    Trp

    W

    Tyrosine

    Tyr

    Y