Biol115
The Thread of Life
Lecture 8
Protein structure
“It now seems certain that the amino acid sequence of any
protein is determined by the sequence of bases in some
region of a particular nucleic acid molecule.”
~Francis Crick, 1962
Principles of Biology
Chapter ‘Proteins’
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Objectives
• Describe the chemical structure of an amino acid.
• Explain the four levels of protein structure.
• Explain the roles played by protein domains, as well as the relationship
between protein domains and exons in genes.
• Associate protein structure to function.
• Key terms: alpha helix, amino acid, beta pleated sheet, catalyst, denaturation,
disulphide bridge, hydrophobic effect, peptide bond, polypeptide, primary
structure, protein, quaternary structure, secondary structure, tertiary structure, Xray crystallography
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RNA and Protein synthesis
Type
Functions in
mRNA Nucleus, migrates to
ribosomes in
cytoplasm
Function
Carries DNA sequence
information to ribosomes
tRNA
Cytoplasm
Provides linkage between
mRNA and amino acids:
transfers amino acids to
ribosome
rRNA
Cytoplasm
Structural component of
ribosomes.
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Proteins have many structures,
resulting in a wide range of functions
• Proteins account for more than 50 % of the dry mass of most cells.
• Protein functions include:
• Metabolism
• Signaling
• Transport
• Structure
• Movement
• Defense.
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Table 5-1
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Polypeptides
• Polypeptides are polymers built from the same set of 20
amino acids.
• A protein consists of one or more polypeptides.
• Non-branching chains of amino acid building blocks
• Polypeptides usually range from 10 to >1000 amino acids in
length
• All share similar structures
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Amino acids
• Amino acids are organic molecules with carboxyl and amino
groups.
• Amino acids differ in their properties due to differing side chains,
called R groups.
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Nonpolar side chains; hydrophobic
Side chain
(R group)
• All 20 amino acids are
identical, except for their Rgroups.
• The unique properties of
individual amino acids are
associated with their Rgroups.
Glycine
(Gly or G)
Alanine
(Ala or A)
Methionine
(Met or M)
Leucine
(Leu or L)
Valine
(Val or V)
Phenylalanine
(Phe or F)
Tryptophan
(Trp or W)
Isoleucine
(Ile or I)
Proline
(Pro or P)
Polar side chains; hydrophilic
Fig. 5-17
Serine
(Ser or S)
Threonine
(Thr or T)
Cysteine
(Cys or C)
Tyrosine
(Tyr or Y)
Electrically charged side chains; hydrophilic
Asparagine
(Asn or N)
Glutamine
(Gln or Q)
Basic (positively charged)
Acidic (negatively charged)
Aspartic acid
(Asp or D)
Glutamic acid
(Glu or E)
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Lysine
(Lys or K)
Arginine
(Arg or R)
Histidine
(His or H)
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Polypeptides
• Amino acids are linked by peptide bonds.
• A polypeptide is a polymer of amino acids.
• Polypeptides range in length from a few to more than a
thousand amino acids.
• Each polypeptide has a unique linear sequence of amino acids.
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Carboxyl (COOH) and amino
(NH3) groups form
peptide bonds to join amino
acids together end to end.
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Protein structure and function
• A functional protein consists of one or more polypeptides
twisted, folded, and coiled into a unique shape.
• The sequence of amino acids determines the threedimensional structure of a protein.
• The structure of a protein determines its function.
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Fig. 5-20
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Four levels of protein structure
• The primary structure of a protein is its unique sequence of
amino acids.
• Secondary structure, found in most proteins, consists of coils and
folds in the polypeptide chain.
• Tertiary structure is their 3-D shape and is determined by
interactions among various side chains (R groups).
• Quaternary structure results when a protein consists of multiple
polypeptide chains.
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Primary structure
Amino
acids
•Primary structure, the sequence
of amino acids in a protein, is like
the order of letters in a long word
•Primary structure is determined
by inherited genetic information
Amino end
Primary structure of transthyretin
Carboxyl end
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Bonds & interactions
involved in protein folding
• Hydrophobic interactions
• Hydrogen bonding
• Disulfide bridges
• Ionic bonding
• Van der Waals forces
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•The coils and folds of
secondary structure result
from hydrogen bonds
between repeating
constituents of the
polypeptide backbone
Tertiary
structure
Secondary
structure
Quaternary
structure
 helix
•Typical secondary
structures are a coil called
an  helix and a folded
structure called a 
pleated sheet
Hydrogen bond
 pleated sheet
 strand
Hydrogen
bond
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Transthyretin
polypeptide
Transthyretin
protein
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• Tertiary structure is determined by
interactions between R groups,
rather than interactions between
backbone constituents
• These interactions between R
groups include hydrogen bonds,
ionic bonds, hydrophobic
interactions, and van der Waals
interactions
Tertiary structure
Transthyretin
polypeptide
• Strong covalent bonds called
disulfide bridges may reinforce the
protein’s structure
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Hydrogen
bond
Hydrophobic
interactions and
van der Waals
interactions
Disulfide
bridge
Ionic bond
Polypeptide
backbone
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Quaternary structure
Haem
Iron
• Quaternary structure results
when two or more polypeptide
chains form one macromolecule
• Collagen is a fibrous protein
consisting of three polypeptides
coiled like a rope
 subunit
 subunit
 subunit
Transthyretin
protein
(four identical
polypeptides)
 subunit
Hemoglobin
• Hemoglobin is a globular protein
consisting of four polypeptides: two
alpha and two beta chains
Collagen
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DOMAINS
• Many polypeptides are modular, with different
modules (regions) of the same polypeptide
performing different functions.
• These specialized modules within a
polypeptide are called domains.
• compact structure and fold independently
of the rest of the polypeptide
• function and evolution
• Genes are often constructed by splicing DNA
for different domains together during evolution.
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Three domains of Thermus
aquaticus elongation factor EF-Tu
protein: in blue (all-β), red (α/β) and
green (all-β). Each domain is
encoded by a separate exon of the
EF-Tu gene.
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Domains are the functional toolkits of
proteins
• There are relatively few unique domains…maybe <500.
• When mixed in different combinations, domains provide all of the biological
functions for life.
• e.g. fibronectin III domain – found in 3427 known proteins
Insulin-like growth factor receptor (muscle growth)
Prolactin receptor (lactation)
Sevenless (eye development)
Contactin 1(nervous system dev’t)
Penicillin binding protein (antibiotic resistance)
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Sickle-cell disease: a change in
primary structure
• A slight change in primary structure can affect a protein
structure and its ability to function.
• Sickle-cell disease, an inherited blood disorder, results from a
single amino acid substitution in the haemoglobin protein.
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Fig. 5-22
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What determines protein structure?
• In addition to primary structure, physical and chemical conditions
can affect structure.
• Alterations in pH, salt concentration, temperature, or other
environmental factors can cause a protein to unravel.
• This loss of the native protein structure is called denaturation.
• A denatured protein is biologically inactive.
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Fig. 5-23
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Protein folding in the cell
• It is hard to predict protein structure from primary structure.
• Most proteins probably go through several states on their way
to a stable structure.
• Chaperonins are protein molecules that assist the proper
folding of other proteins.
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Fig. 5-24
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Protein degradation
• Proteasomes are giant protein complexes that bind protein
molecules and degrade them
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Diseases due to protein misfolding
Disease
Genetic causes
Function
APP
Gives rise to Aβ, the primary component of senile plaques
PS1 and PS2
A component of γ-secretase, which cleaves APP to yield Aβ
Parkinson's disease
α-Synuclein
The primary component of Lewy bodies
Parkinson's disease
Parkin
A ubiquitin E3 ligase
Parkinson's disease
DJ-1
Protects the cell against oxidant-induced cell death
Parkinson's disease
PINK1
A kinase localized to mitochondria. Function unknown. Seems to protect against
cell death
Parkinson's disease
LRRK2
A kinase. Function unknown
Parkinson's disease
HTRA2
A serine protease in the mitochondrial intermembrane space. Degrades denatured
proteins within mitochondria. Degrades inhibitor of apoptosis proteins and
promotes apoptosis if released into the cytosol
Amyotrophic lateral
sclerosis
SOD1
Converts superoxide to hydrogen peroxide. Disease-causing mutations seem to
confer a toxic gain of function
Huntington's disease
Huntingtin
Function unknown. Disease-associated mutations produce expanded
polyglutamine repeats
Alzheimer's disease
Parkinson's disease
Lin, M. T. & Beal, M. F. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443, 787–795 (2006)
doi:10.1038/nature05292.
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Protein misfolding and Alzheimer’s
disease
Tau protein
http://eecs-newsletter.mit.edu/wp-content/uploads/2009/11/07_Labnotes_RLE_huge2.png
Science, 295:1852-1858 (2002)
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X-ray crystallography
• Important technique in
determining protein structure
• Measures angle and intensity
with which X-rays are diffracted
when passing through a
crystalline structure.
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Crystal structure of the glutamate receptor –
involved in neurotransmission (memory)
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You should now be able to:
1. Explain how the chemical natures of the different amino acids are
determined.
2. Understand the different roles that proteins play in living
organisms.
3. Describe the four levels of protein structure and how structure is
related to function in proteins.
4. Explain the role of protein domains.
5. Distinguish between the terms “polypeptide” and “proteins”.
6. Describe a method that is used to determine the structure of
proteins.
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