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Transcript
14
From DNA to Protein:
Gene Expression
14 From DNA to Protein: Gene Expression
14.1 What Is the Evidence that Genes
Code for Proteins?
14.2 How Does Information Flow from
Genes to Proteins?
14.3 How Is the Information Content in
DNA Transcribed to Produce
RNA?
14 From DNA to Protein: Gene Expression
14.4 How Is Eukaryotic DNA
Transcribed and the RNA
Processed?
14.5 How Is RNA Translated into
Proteins?
14.6 What Happens to Polypeptides
after Translation?
14 From DNA to Protein: Gene Expression
Methicillin-resistant Staphylococcus
aureus (MRSA) is now a major cause
of serious illness and death.
It is treated with antibiotics such as
tetracycline that target its gene
expression, but many strains are now
becoming resistant to tetracycline.
Opening Question:
Can new treatments focused on gene
expression control MRSA?
14.1 What Is the Evidence that Genes Code for Proteins?
The molecular basis of phenotypes
was discovered before it was known
that DNA is the genetic material.
Studies of many different organisms
showed that major phenotypic
differences were due to differences in
specific proteins.
14.1 What Is the Evidence that Genes Code for Proteins?
Identification of gene products as
proteins began with studies of
alkaptonuria, a disease in children.
It was more common in children of first
cousins. A recessive mutant allele
was inherited from both parents.
The mutation produced homogentisic
acid, which accumulated in blood,
joints, and urine, and turned the urine
dark brown.
14.1 What Is the Evidence that Genes Code for Proteins?
Homogentisic acid (HA) is a
breakdown product of the amino acid
tyrosine; it is normally converted to a
harmless product by an enzyme.
14.1 What Is the Evidence that Genes Code for Proteins?
When the allele is mutated, the
enzyme is inactive, and HA
accumulates.
Thus, the researchers correlated one
gene to one enzyme.
Confirmation required identification of
the specific enzyme and gene
mutation, which occurred much later.
Biologists turned to model organisms
to understand gene expression.
14.1 What Is the Evidence that Genes Code for Proteins?
Model organisms:
• Easy to grow in the laboratory
• Short generation times
• Easy to manipulate genetically
• Produce large numbers of progeny
Examples: Pea plants, Drosophila, E.
coli, and common bread mold—
Neurospora crassa.
14.1 What Is the Evidence that Genes Code for Proteins?
Neurospora is haploid for most of its
life cycle, so there are no dominant or
recessive alleles.
Beadle and Tatum used Neurospora to
test the one-gene, one-enzyme
hypothesis.
Wild-type Neurospora strains have
enzymes to catalyze all the reactions
needed for growth.
14.1 What Is the Evidence that Genes Code for Proteins?
Mutations were induced with X-rays as
the mutagens—something that
damages DNA and causes
mutations—heritable alterations in
DNA sequences.
The mutant strains needed additional
nutrients, such as vitamins, to grow.
14.1 What Is the Evidence that Genes Code for Proteins?
Each mutant strain required only one
additional nutrient.
Results suggested that each mutation
caused a defect in only one enzyme
in a metabolic pathway, confirming
the one-gene, one-enzyme
hypothesis.
14.1 What Is the Evidence that Genes Code for Proteins?
Mutations are a powerful tool to
determine cause and effect, and have
been used to determine metabolic
pathways.
If a gene determines synthesis of one
enzyme, mutating that gene will
result in a nonfunctional enzyme, and
the reaction doesn’t occur—stopping
the pathway at that point.
Figure 14.1 One Gene, One Enzyme
14.1 What Is the Evidence that Genes Code for Proteins?
One-gene, one-enzyme has since
been revised to the one-gene, onepolypeptide relationship.
Many proteins have several
polypeptides chains, or subunits.
Example: Hemoglobin has four
subunits, each specified by a
separate gene.
Not all genes code for polypeptides.
Working with Data 14.1: One Gene, One Enzyme
To test the one-gene, one-enzyme
hypothesis, X-rays were used to
cause mutations in Neurospora.
Fifteen mutant strains were produced
that could not synthesize arginine,
but some strains could grow if
supplied with ornithine and citrulline.
These compounds are intermediates in
the metabolic pathway that
synthesizes arginine.
Working with Data 14.1: One Gene, One Enzyme
The 15 mutant strains were tested for
growth in the presence of the other
substances:
Growth is expressed as dry weight of fungal
material after five days.
Working with Data 14.1: One Gene, One Enzyme
Question 1:
Based on the biochemical pathway
for arginine synthesis shown in
Figure 14.1, which enzyme (A, B, or
C) was mutated in each strain?
Figure 14.1 One Gene, One Enzyme
Working with Data 14.1: One Gene, One Enzyme
Question 2:
Why was there some growth in
strains 34105 and 33442 even when
there were no additions to the growth
medium?
Working with Data 14.1: One Gene, One Enzyme
Question 3:
Nineteen other amino acids were
tested as substitutes for arginine in
the three strains. In all cases, there
was no growth.
Explain these results.
Working with Data 14.1: One Gene, One Enzyme
Question 4:
Sexual reproduction in Neurospora was
used to create double mutants, which
carried the mutations from both parental
strains.
A double mutant derived from strains
33442 and 36703 had the growth
characteristics shown in the table.
Explain these data in terms of the genes,
mutations, and biochemical pathway.
14.2 How Does Information Flow from Genes to Proteins?
Gene expression occurs in two steps:
• Transcription: DNA sequence is
copied to a complementary RNA
sequence
• Translation: RNA sequence is
template for an amino acid sequence
14.2 How Does Information Flow from Genes to Proteins?
This model was proposed by Crick and
Watson, and called “The central
dogma of molecular biology.”
14.2 How Does Information Flow from Genes to Proteins?
Three kinds of RNA are involved in
gene expression:
1. Messenger RNA (mRNA) and
transcription:
One strand of DNA is copied to a
complementary mRNA strand. In
eukaryotes, the mRNA moves to the
cytoplasm.
14.2 How Does Information Flow from Genes to Proteins?
2. Ribosomal RNA (rRNA) and
translation:
Ribosomes are protein synthesis
factories made up of proteins and
rRNA.
rRNA catalyzes peptide bond
formation between amino acids, to
form a polypeptide.
14.2 How Does Information Flow from Genes to Proteins?
3. Transfer RNA (tRNA):
Can bind a specific amino acid, and
recognize specific sequences in
mRNA.
tRNA recognizes which amino acid
should be added next to a growing
polypeptide chain.
14.2 How Does Information Flow from Genes to Proteins?
The central dogma suggested that
information flows from DNA to RNA
to protein, which raised two
questions:
• How does genetic information get
from the nucleus to the cytoplasm?
• What is the relationship between a
DNA sequence and an amino acid
sequence?
Figure 14.2 From Gene to Protein
14.2 How Does Information Flow from Genes to Proteins?
Some viruses are exceptions: they
have RNA instead of DNA.
Most replicate by transcribing RNA to
a complementary RNA strand, which
then makes multiple copies of the
viral genome.
14.2 How Does Information Flow from Genes to Proteins?
Retroviruses, such as HIV, make a
DNA copy of their genome—reverse
transcription.
The host cell transcription machinery
makes more RNA, resulting in new
viral particles.
14.3 How Is the Information Content in DNA Transcribed to
Produce RNA?
Transcription requires:
• A DNA template for base pairings
• The four ribonucleoside
triphosphates
(ATP,GTP,CTP,UTP)
• An RNA polymerase
• Salts and pH buffer, if done in a
test tube
14.3 How Is the Information Content in DNA Transcribed to
Produce RNA?
Transcription produces mRNA, tRNA,
and rRNA.
These RNAs are encoded by specific
genes.
Eukaryotes also make several small
RNAs, including small nuclear RNA
(snRNA), microRNA (miRNA), and
small interfering RNA (siRNA).
Table 14.1
14.3 How Is the Information Content in DNA Transcribed to
Produce RNA?
RNA polymerases catalyze synthesis
of RNA:
• Catalyze addition of nucleotides in a
5′-to-3′ direction
• Processive—one enzyme-template
binding results in polymerization of
hundreds of RNA bases
• They do not need primers
Figure 14.3 RNA Polymerase
14.3 How Is the Information Content in DNA Transcribed to
Produce RNA?
Transcription occurs in three phases:
1. Initiation:
RNA polymerase binds to a DNA
sequence called a promoter.
Promoters tell the enzyme where to
start and which strand of DNA to
transcribe.
The promoter has an initiation site
where transcription begins.
Figure 14.4 DNA Is Transcribed to Form RNA (A)
Figure 14.4 DNA Is Transcribed to Form RNA (A)
14.3 How Is the Information Content in DNA Transcribed to
Produce RNA?
Sigma factors and transcription
factors are proteins that bind to DNA
sequences and to RNA polymerase.
They help direct the polymerase onto
the promoter, and help determine
which genes are expressed at
particular times.
14.3 How Is the Information Content in DNA Transcribed to
Produce RNA?
2. Elongation:
RNA polymerase unwinds DNA about
10 base pairs at a time; reads
template in 3′ to 5′ direction.
The transcript is antiparallel to the
DNA template strand.
RNA polymerases do not proofread
and correct mistakes.
Figure 14.4 DNA Is Transcribed to Form RNA (B)
14.3 How Is the Information Content in DNA Transcribed to
Produce RNA?
RNA polymerase uses
(ribo)nucleoside triphosphates
(NTPs) as substrates.
Two phosphate groups are removed
from each substrate molecule; the
energy released is used to drive the
polymerization reaction.
14.3 How Is the Information Content in DNA Transcribed to
Produce RNA?
3. Termination:
Specified by a specific DNA sequence.
Mechanism in eukaryotes is not well
understood.
In bacteria, the transcript forms a loop
and falls away from the DNA; or a
helper protein binds to the transcript
and causes it to detach from the
DNA.
Figure 14.4 DNA Is Transcribed to Form RNA (C)
14.3 How Is the Information Content in DNA Transcribed to
Produce RNA?
The genetic code specifies which
amino acids will be used to build a
protein.
Codon: a sequence of three bases,
something like a three-letter “word.”
Each codon specifies a particular
amino acid.
14.3 How Is the Information Content in DNA Transcribed to
Produce RNA?
How was the code deciphered?
How could 20 “code words” (amino
acids) be written with only four
“letters” (the four bases)?
A triplet code seemed likely; it could
result in 4 × 4 × 4 = 64 codons.
14.3 How Is the Information Content in DNA Transcribed to
Produce RNA?
Nirenberg and Matthaei used simple
artificial mRNAs of known
composition to identify the
polypeptide that resulted.
This led to the identification of the first
three codons.
Figure 14.5 Deciphering the Genetic Code
14.3 How Is the Information Content in DNA Transcribed to
Produce RNA?
Later, scientists used artificial mRNAs
only three nucleotides long (one
codon).
These would bind to a ribosome and a
corresponding tRNA carrying an
amino acid.
Thus the codes for all the amino acids
were determined.
Figure 14.6 The Genetic Code
14.3 How Is the Information Content in DNA Transcribed to
Produce RNA?
There are more codons than amino
acids.
AUG is the start codon—initiation
signal for translation.
Stop codons—termination signals,
include UAA, UAG, and UGA.
14.3 How Is the Information Content in DNA Transcribed to
Produce RNA?
For most amino acids, there is more
than one codon: the genetic code is
redundant.
The genetic code is not ambiguous—
each codon specifies only one amino
acid.
14.3 How Is the Information Content in DNA Transcribed to
Produce RNA?
The genetic code is nearly universal:
The codons that specify amino acids
are the same in all organisms.
A few exceptions: Within mitochondria
and chloroplasts, and in one group of
protists, there are codon differences.
14.3 How Is the Information Content in DNA Transcribed to
Produce RNA?
This common genetic code is also a
common language for evolution.
The code is ancient and has remained
intact throughout evolution.
The common code also allows genetic
engineering—human genes can be
expressed in E. coli, for example.
14.3 How Is the Information Content in DNA Transcribed to
Produce RNA?
The base sequence of the DNA strand
that is transcribed is complementary
and antiparallel to the mRNA codons.
The non-template DNA strand has the
same sequence as the mRNA and is
called the “coding strand.”
By convention, DNA sequences are
shown beginning with the 5′ end of
the coding sequence.
14.4 How Is Eukaryotic DNA Transcribed and the RNA
Processed?
Gene expression is basically the same
in prokaryotes and eukaryotes.
But there are differences in gene
structure:
• In eukaryotes, the nucleus separates
transcription and translation.
Table 14.2
14.4 How Is Eukaryotic DNA Transcribed and the RNA
Processed?
mRNA sequences are complementary to
gene sequences. This can be shown by
nucleic acid hybridization:
DNA is denatured to separate strands.
An mRNA strand called a probe is
incubated with the denatured DNA.
If the probe has a complementary
sequence, base pairing forms a hybrid.
Figure 14.7 Nucleic Acid Hybridization and Introns (Part 1)
14.4 How Is Eukaryotic DNA Transcribed and the RNA
Processed?
Hybridization experiments can be
performed with various combinations
of DNA and RNA.
The probe may be labeled in some
way to detect binding to a specific
target sequence.
The double-stranded hybrids can be
viewed by electron microscopy.
14.4 How Is Eukaryotic DNA Transcribed and the RNA
Processed?
When mRNA probes from prokaryotes
are incubated with their DNAs and
viewed under an electron
microscope, there is a 1:1
complementarity.
In eukaryotes, loops of DNA are often
observed—indicating stretches of
DNA that don’t have a
complementary mRNA sequence.
14.4 How Is Eukaryotic DNA Transcribed and the RNA
Processed?
If the initial mRNA transcript
(precursor or pre-mRNA) is
hybridized with DNA, there is full,
linear, loop-free hybridization.
The intervening regions (introns) get
transcribed then sliced out of premRNA in the nucleus.
Only expressed sequences (exons)
reach the ribosome.
Figure 14.7 Nucleic Acid Hybridization and Introns (Part 2)
Figure 14.8 Transcription of a Eukaryotic Gene
14.4 How Is Eukaryotic DNA Transcribed and the RNA
Processed?
Introns interrupt but do not scramble
the DNA sequence that encodes a
polypeptide.
Sometimes the separated exons code
for different domains (functional
regions) of the protein.
14.4 How Is Eukaryotic DNA Transcribed and the RNA
Processed?
In the nucleus, pre-mRNA is modified:
• A 5′ cap is added at the 5′ end. The
cap is a modified GTP which
facilitates mRNA binding to a
ribosome.
Also protects mRNA from being
digested by ribonucleases.
14.4 How Is Eukaryotic DNA Transcribed and the RNA
Processed?
• A poly A tail is added at 3′ end.
AAUAAA sequence after last codon
is a signal for an enzyme to cut the
pre-mRNA; then another enzyme
adds 100 to 300 adenines—the “tail.”
The tail assists in export from the
nucleus and is important for stability
of mRNA.
Figure 14.9 Processing the Ends of Eukaryotic Pre-mRNA
14.4 How Is Eukaryotic DNA Transcribed and the RNA
Processed?
• Introns are then removed.
RNA splicing removes introns and
splices exons together.
snRNPs (small nuclear
ribonucleoprotein particles) bind to
ends of introns at consensus
sequences—short DNA stretches
that appear in many genes.
Figure 14.10 The Spliceosome: An RNA Splicing Machine
14.4 How Is Eukaryotic DNA Transcribed and the RNA
Processed?
With energy from ATP, proteins are
added to form an RNA-protein
complex, the spliceosome.
The complex cuts pre-mRNA, releases
introns, and splices exons together to
produce mature mRNA.
14.4 How Is Eukaryotic DNA Transcribed and the RNA
Processed?
In the disease β-thalassemia, a
mutation may occur at an intron
consensus sequence in the β-globin
gene—the pre-mRNA cannot be
spliced correctly.
Non-functional β-globin mRNA is
produced.
14.4 How Is Eukaryotic DNA Transcribed and the RNA
Processed?
Mature mRNA leaves the nucleus
through nuclear pores.
A cap-binding protein complex binds to
the 5′ cap and to other proteins that
are recognized by receptors at the
nuclear pore.
These proteins lead the mRNA
through the pore; unused pre-mRNAs
stay in the nucleus.
14.5 How Is RNA Translated into Proteins?
Transfer RNA (tRNA) links mRNA
codons with specific amino acids.
There is at least one specific tRNA
molecule for each of the 20 amino
acids.
14.5 How Is RNA Translated into Proteins?
Each tRNA has three functions:
• It binds to a specific enzyme that
attaches it to only one amino acid: it
is then “charged”
• Binds to mRNA at a triplet called the
anticodon, which is complementary
to an mRNA codon
• Interacts with ribosomes
Figure 14.11 Transfer RNA
14.5 How Is RNA Translated into Proteins?
Wobble: Specificity for the base at the
3′ end of the codon is not always
observed.
Example: Codons for alanine—GCA,
GCC, and GCU—are recognized by
the same tRNA.
Wobble allows cells to produce fewer
tRNA species, but does not allow the
genetic code to be ambiguous.
14.5 How Is RNA Translated into Proteins?
tRNAs are charged by aminoacyltRNA synthetases.
Each enzyme is specific for one amino
acid and its corresponding tRNA.
Charging requires ATP; a high-energy
bond forms between the amino acid
and the tRNA—it is later used to form
the peptide bond.
Figure 14.12 Charging a tRNA Molecule
14.5 How Is RNA Translated into Proteins?
Specificity between the tRNA and its
amino acid is extremely important.
Experiments showed that specificity is
at the anticodon:
Cysteine already bound to tRNA was
chemically changed to alanine.
Everywhere cysteine was supposed
to be in the polypeptide, alanine
appeared instead.
14.5 How Is RNA Translated into Proteins?
Translation occurs at a ribosome.
It holds mRNA and charged tRNAs in
the correct position to allow assembly
of the polypeptide.
Ribosomes can make any type of
protein, they can be used over and
over. Most cells have thousands of
them.
14.5 How Is RNA Translated into Proteins?
Ribosomes have two subunits, large
and small, held together noncovalently.
In eukaryotes, the large subunit has
three different molecules of ribosomal
RNA (rRNA) and 49 different proteins
in a precise pattern.
The small subunit has one rRNA and
33 proteins.
Figure 14.13 Ribosome Structure
14.5 How Is RNA Translated into Proteins?
Ribosomal proteins and RNAs are
different in prokaryotes.
This explains why antibiotics that
target prokaryotic ribosomes (such as
tetracycline) kill bacteria without
harming the patient’s cells.
Mitochondria and chloroplasts also
have ribosomes, similar to those of
prokaryotes.
14.5 How Is RNA Translated into Proteins?
A large subunit has three tRNA
binding sites:
• A (aminoacyl tRNA) site binds with
anticodon of charged tRNA
• P (peptidyl tRNA) site where tRNA
adds its amino acid to the growing
chain
• E (exit) site where tRNA sits before
being released from the ribosome
14.5 How Is RNA Translated into Proteins?
Ribosomes have a fidelity function: When
proper binding occurs, hydrogen bonds
form between the base pairs of the
anticodon and the mRNA codon.
Small subunit rRNA validates the match—if
hydrogen bonds have not formed between
all three base pairs, the tRNA must be an
incorrect match for that codon and the
tRNA is rejected.
14.5 How Is RNA Translated into Proteins?
Translation occurs in three steps:
1. Initiation
An initiation complex forms—a
charged tRNA and small ribosomal
subunit, both bound to mRNA.
In prokaryotes rRNA binds to the
Shine-Dalgarno sequence on the
mRNA.
In eukaryotes it binds to the 5′ cap.
Figure 14.14 The Initiation of Translation
14.5 How Is RNA Translated into Proteins?
mRNA start codon is AUG
A tRNA charged with methionine
(anticodon UAG) binds to complete
the initiation complex.
First amino acid in a polypeptide is
always methionine, which may be
removed after translation.
14.5 How Is RNA Translated into Proteins?
The large subunit joins the complex;
the charged tRNA is now in the P
site.
The A site is aligned with the second
mRNA codon.
Initiation factors are responsible for
assembly of the initiation complex.
14.5 How Is RNA Translated into Proteins?
2. Elongation
Another charged tRNA enters A site
and the large subunit catalyzes two
reactions:
• Bond between tRNA in P site and its
amino acid is broken
• Peptide bond forms between that
amino acid and the amino acid on
tRNA in the A site
Figure 14.15 The Elongation of Translation (Part 1)
14.5 How Is RNA Translated into Proteins?
The large subunit has peptidyl
transferase activity.
RNA was shown to be the catalyst by:
• Removing the proteins from the large
subunit – it still catalyzed peptide
bonds
• Modifying rRNA, which destroyed
peptidyl transferase activity
Figure 14.15 The Elongation of Translation (Part 2)
14.5 How Is RNA Translated into Proteins?
Purification and crystallization of
ribosomes has allowed scientists to
confirm the catalytic role of rRNA.
This supports the hypothesis that
RNA, and catalytic RNA in particular,
evolved before DNA.
14.5 How Is RNA Translated into Proteins?
When the first tRNA has released its
methionine, it moves to the E site and
dissociates from the ribosome.
The tRNA can be charged again.
Elongation occurs as the steps are
repeated, assisted by proteins called
elongation factors.
14.5 How Is RNA Translated into Proteins?
3. Termination
Translation ends when a stop codon
enters the A site.
Stop codons bind a protein release
factor which hydrolyzes bond
between the polypeptide and the
tRNA in the P site.
The polypeptide then separates from
the ribosome.
Figure 14.16 The Termination of Translation (Part 1)
Figure 14.16 The Termination of Translation (Part 2)
Figure 14.16 The Termination of Translation (Part 3)
Table 14.3
14.5 How Is RNA Translated into Proteins?
Several ribosomes can work together
to translate the same mRNA,
producing multiple copies of the
polypeptide.
A strand of mRNA with associated
ribosomes is called a polyribosome,
or polysome.
Figure 14.17 A Polysome
14.6 What Happens to Polypeptides after Translation?
After translation, polypeptides may
move into an organelle, or out of the
cell.
They are often modified by the addition
of new chemical groups that affect
their function.
14.6 What Happens to Polypeptides after Translation?
Polypeptide emerges from the
ribosome and folds into its 3-D
shape.
It may contain a signal sequence
indicating where in the cell it belongs.
If there is no signal sequence, it
remains where it was synthesized.
Figure 14.18 Destinations for Newly Translated Polypeptides in a Eukaryotic Cell
14.6 What Happens to Polypeptides after Translation?
A signal sequence binds to a receptor
protein on the surface of an
organelle.
A channel forms in the organelle
membrane and the protein enters.
Example: a nuclear localization signal
(NLS)—
-Pro-Pro-Lys-Lys-Lys-Arg-Lys-Val-
14.6 What Happens to Polypeptides after Translation?
The nuclear localization signal was
determined by making proteins with
and without the signal sequence,
then injecting them into cells.
Only proteins with the signal ended up
in the nucleus.
Figure 14.19 Testing the Signal
14.6 What Happens to Polypeptides after Translation?
Some polypeptides have a signal
sequence that stops translation and
sends the ribosome to the
endoplasmic reticulum.
Ribosome binds to the ER and
translation resumes. The polypeptide
will move into the ER lumen.
14.6 What Happens to Polypeptides after Translation?
Inclusion-cell (I-cell) disease is caused
by a mutation in a gene encoding a
Golgi enzyme that adds a signal to
proteins destined for the lysosomes.
Without a signal, enzymes that
hydrolyze macromolecules in the
lysosome can’t get there.
Molecules build up and are not
recycled.
14.6 What Happens to Polypeptides after Translation?
Most polypeptides are modified after
translation:
• Proteolysis: Polypeptide is cut by
proteases, (e.g., signal sequence is
removed)
• Glycosylation: Addition of sugars to
form glycoproteins. The sugars can
act as signals; others form membrane
receptors
14.6 What Happens to Polypeptides after Translation?
• Phosphorylation: Addition of
phosphate groups catalyzed by
protein kinases
The charged phosphate groups
change the conformation and may
expose active sites or binding sites.
Figure 14.20 Posttranslational Modifications of Proteins
14 Answer to Opening Question
A different type of antibiotic is being
developed that targets mRNA breakdown.
mRNA is broken down after use and quickly
recycled, so that bacteria can adapt rapidly
to changing environments.
The antibiotic targets a protein that is part of
the breakdown machinery—without it, the
cell can’t recycle mRNA.
MRSA is particularly sensitive to this
molecule.