Protein Structure,
Classification and Functions
Likando Chababa
What are proteins?
n Proteins are polymers of amino acids
joined together by peptide bonds
n
PROTEINS
Proteins are macromolecules with a backbone formed by polymerization
of amino acids in a polyamide structure which constitute more than 50%
of the total dry body weight.
n They all contain C, H, O and N.
n Nearly all of them contain S and some have Cu, Zn, Fe and P.
n Different combination of amino acids infer different function of the
protein.
n Describing and understanding structure of proteins we need to approach
at several levels of complexity, arranged in a kind of conceptual
hierarchy.
n Four levels of protein structure are commonly defined.
Primary Structure
n It is the linear sequence of amino acids
A description of all covalent bonds (mainly peptide bonds
and disulphide bonds) linking amino acid residues in a
polypeptide chain is its primary structure.
Most important element of 1° structure is the sequence of
amino acids
Primary Structure of
n The primary structure of a proteinProteins
is defined by the linear
sequences of amino acid residues.
n Protein contain between 50 and 2000 amino acid residues.
n The amino acid composition of a peptide chain has a
profound effect on its physical and chemical properties of
proteins.
n The higher levels of protein organisation; 2°, 3° and 4°
will be decided by the primary structure.
n Mutation in the 1° structure will have profound effects on
the 2°, 3° and 4° protein.
n For example, sickle cell anaemia caused by absence of 6th
amino acid in haemoglobin (Hb) which is Glutamic acid
being replaced by Valine.
Primary Structure of
Proteins
n The 1° structure is maintained by covalent bonds of peptide
linkages (refer to peptide bond formation) and most are linear but
others are branched or circular.
n Insulin is branched; branches are produced by the disulphide
bridges.
n Insulin has two chains; the A-chain (Glycine chain) and the B-
chain (Phenylalanine chain).
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Primary structure of proinsulin
Secondary Structure
n It is the local spartial arrangement of
a polypeptide backbone
n Geometric patterns formed on
specific segments of a pp chain
n Excluding the conformations (3D
arrangements) of its side chains
a Helix
n a helix is right-handed
n It has 3.6 residues (amino acids) per turn
n The helix is stabilized by hydrogen bonding
u Between carboxylic group and 4th N–H
group
n The amino acid side chains point outward
and downward from the helix
n The core of the helix is tightly packed; its
atoms are in van der Waals contact
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The right-handed a helix
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B pleated Sheets
n Two or more polypeptide chains form
hydrogen bonding with each other
n They appear as folded structures with
edges
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A two-stranded b antiparallel pleated sheet
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Antiparallel b sheets
n Two or more hydrogen-bonded
polypeptide chains run in opposite
direction
n Hydrogen bonding is more stable
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b pleated sheets. (a) The antiparallel b pleated sheets
Parallel b sheets
n Two or more hydrogen-bonded
polypeptide chains run in the same
direction
n Hydrogen bonding is less stable
(distorted)
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b pleated sheets. (b) The parallel b pleated sheets.
Other secondary
structures
n Turns (reverse turns)
n Loops
n b bends
n Random coils
n Supersecondary structures or motifs:
ubab motif: a helix connects two b
sheets
ub hairpin: reverse turns connect
antiparallel b sheets
uaa motif: two a helices together
ub barrels: rolls of b sheets
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bab motif b hairpin aa motif
© 2004 John Wiley & Sons, Inc.
Schematic diagrams of supersecondary structures
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b barrel
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Secondary structure of proteins
(a-helix, b-sheets, loops, turns, random coils)
Tertiary Structure
n It is the three-dimensional structure
of an entire polypeptide chain
including side chains
n It is the overall folding of secondary
structure and side chains as a result
of various forces not just H bonds
n Helices, sheets and side chains
combined to form tertiary structure
The three dimensional, 3-D, folded and Four types
Tertiary Structure
n
of interactions cooperate in stabilizing the tertiary
structures of globular proteins:
1. Hydrogen bonds
2. Hydrophobic bonds
3. Disulphide bridges
4. Salt/ionic bonds
1. Hydrogen bonds: Tertiary Structure
u A.A side chains containing oxygen- or nitrogen-
bound hydrogen, such as:
« alcoholgroups of ser, thr and tyr, can form hydrogen
bonds with electron-rich atoms, such as:
« Oxygen of a carboxyl group (Glu, Asp) or carbonyl
group of a peptide bond or the free one from Asn and
Gln
2. Hydrophobic bonds:
u [Link] with nonpolar side chains tend to be located in
the interior of the polypeptide molecule, where they
associate with other hydrophobic amino acids
3. Ionic bonds/Salt bridges:
u
Tertiary Structure
Negatively charged groups, such as the carboxyl group
in the side chain of Asp or Glu, can interact with
positively charged groups, such as the amino group in
the side chain of lys or Arg.
4. Disulphide bonds:
u Covalent linkage formed from the sulfhydryl group (-
SH) of each of two cys residues, to produce a cysteine
residue.
Tertiary Structure
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Tertiary structure of proteins
(Secondary structure + side chains)
n Domains
uPolypeptide chains (>200 amino
acids) fold into two or more clusters
known as domains
uDomains are units that look like
globular proteins
uDomains are part of protein subunits
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One subunit with two domains
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One subunit with three domains
Quaternary Structure
n Many proteins contain two or more
polypeptide chains
n Each chain forms a three-dimensional
structure called subunit
n It is the 3D arrangement of different
subunits of a protein
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Forces that stabilize
protein structure
n Hydrophobic effect:
uNonpolar groups to minimize their
contacts with water
uNonpolar side chains are in the
interior of a protein
n Hydrogen bonding
n Electrostatic interactions (ion pairing
a.k.a salt bridges):
uBetween positive and negative
charges
n van der Waals forces (weak polar
forces):
uWeak attractive or repulsive forces
between molecules
Protein denaturation
n Denaturation: A process in which a protein looses its
native structure
n Factors that cause denaturation:
u Heat: disrupts hydrogen bonding
u Change in pH: alters ionization states of aa
u Detergents: interfere with hydrophobic interactions
u Chaotropic agents: ions or small organic molecules
that disrupt hydrophobic interactions
Protein misfolding
n Every protein must fold to achieve its
normal conformation and function
n Abnormal folding of proteins leads to a
number of diseases in humans
Alzheimer’s disease:
n b-amyloid protein is a misfolded protein
n It forms fibrous deposits or plaques in the
brains of Alzheimer’s patients
Creutzfeldt-Jacob or prion disease:
n Prion protein is present in normal brain
tissue
n In diseased brains, the same protein is
misfolded
n Therefore it forms insoluble fibrous
aggregates that damage brain cells
Classification of proteins based on
various criteria
1. Based on Function
a.
«
Classification of Proteins
Catalytic proteins:
Enzymes form the most varied and mostly highly specialized
group of proteins and also represents the largest group of
protein.
b. Structural proteins:
« Collagen serves as the major structure protein in connective
tissue and bone.
« It is rigid, insoluble and consists of α chains wrapped around
each other in a triple helix to form a rope-like structure.
« Keratin is found in hair, finger nails.
c. Contractile proteins:
« Endow cells and organisms to contract, change shape and
move about e.g. myosin and actin.
« Filamentous proteins in contractile systems of skeletal muscles
and many non-muscle cells.
d.
Classification of Proteins –
Transport proteins:
Based on function
« Bind and carry specific molecules or ions via blood to different
organs e.g. Hb and albumin.
e. Regulatory proteins:
« Regulate cellular or physiologic activities e.g. insulin which
regulates sugar metabolism.
« If deficient one has Diabetes mellitus
f. Nutrient and storage proteins:
« Store amino acids as nutrients for growing embryos e.g. albumin
of the egg white.
g. Genetic proteins:
« Histones involved in DNA packaging and folding in the nucleus.
h. Defensive proteins:
« Protect organisms against invasion by other species and include
immunoglobulins (Antibodies), fibrinogen and thrombin.
Based on Composition
Classification of Proteins
2.
a. Simple proteins
« On hydrolysis, they yield only amino acids.
b. Conjugated proteins
« Yield other organic or inorganic in addition to amino
acids e.g. glycoproteins, lipoproteins and
phosphoproteins.
« The non-protein part is called the prosthetic group.
« Metalloproteins contain metal ions e.g. Hb contain Fe.
Conjugated proteins
Conjugated proteins on hydrolysis, give a protein part and non protein part and subclassified into:
1- Phosphoproteins: These are proteins conjugated with phosphate group.
2- Lipoproteins: These are proteins conjugated with lipids.
3- Glycoproteins: proteins conjugated with sugar (carbohydrate)
4- Nucleoproteins: These are basic proteins (e.g. histones) conjugated with nucleic acid (DNA or RNA).
5- Metalloproteins: These are proteins conjugated with metal like iron, copper, zinc, ……
a- Iron-containing proteins: Iron may be present in heme such as in
- hemoglobin (Hb)
- myoglobin ( protein of skeletal muscles and cardiac muscle),
- cytochromes,
- catalase, peroxidases (destroy H2O2)
- tryptophan pyrrolase (desrtroy indole ring of tryptophan).
Iron may be present in free state ( not in heme) as in:
- Ferritin: Main store of iron in the body. ferritin is present in liver, spleen and bone marrow.
- Hemosidrin: another iron store.
- Transferrin: is the iron carrier protein in plasma.
b- Copper containing proteins:
e.g. - Ceruloplasmin which oxidizes ferrous ions into ferric ions.
- Oxidase enzymes such as cytochrome oxidase.
c- Zn containing proteins: e.g. Insulin
d- Mg containing proteins: e.g. Kinases
3. Based on Shape
a. Globular proteins:
Spherical or ovoid shape and are easily
soluble e.g. Hb
b. Fibrous proteins:
Are elongated with minimal solubility and are
resistant to digestion e.g. keratin.