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PROTEIN

STRUCTURE
ROLE IN HUMAN
DISORDERS
COURTNEY S. ZAHN

IMPORTANCE OF PROTEINS
Proteins are macromolecules involved in every aspect of all
living things.
Without proteins, Biology as we know it would not exist.
Proteins are the most versatile macromolecules.
Proteins constitute over 50% of dry weight of cells.

BASIC PROTEIN FUNCTIONS


- Provide cell structure.
- Take nutrients into cell.
- Control biochemical reactions.
- Contract muscle.
- Carry out immune responses.

- Impact human disorders.

COMPOSITION OF PROTEINS
AMINO ACIDS
-

20 or more major amino acids, which are produced based on


genetic information in a cell.

Amino acids can be arranged in numerous combinations.

Protein properties depend mainly on the shape and arrangement


of these amino acids.

Each protein is unique in its number and order of amino acids.

Of the many amino acid combinations, only 1 shape is functional


for each protein.

AMINO ACIDS
- Peptide bonds are a special covalent bond which link
amino acids together in proteins to form a polypeptide
chain.
- Some proteins are a single polypeptide chain, and
others consist of multiple chains held together by weak
bonds.
- Formation of proteins is rapid.
- Polypeptide chains are formed and folded into their
correct shapes in a matter of seconds.

AMINO ACIDS AND PROTEIN STRUCTURE


AMINO ACIDS COOH (an acid group), --NH2 (an amino group), and a
side chain which confers unique properties on the amino acid (R
group)

Four levels of protein structure:


Primary amino acid sequence
Secondary determined by intramolecular bonding between amino
acids
Tertiary the final 3-D shape of a protien caused from the coiling and
folding of polypeptides to form an alpha helix or a pleated beta
sheet
Quaternary - the interaction of multiple polypeptide chains.

DENATURING OF PROTEINS
Conditions which can cause proteins to denature:

High Temperatures
Alkalosis
Acidosis
Osmotic Shock
Oxidative Stress

DENATURED PROTEINS FROM EVERYDAY


LIFE

DENATURING OF PROTEINS
These environmental stressors break down proteins,
changing their structures, and re-directing their fate.
The result is a NONFUNCTIONING protein.
Sometimes denaturation is reversible (chemical denaturing
agent removal). In these cases, the protein can
spontaneously refold into its original functional state.

In other cases, it is irreversible.

PROTEIN FOLDING PROBLEM


- Proteins are responsible for the properties of all
organisms.
- Correct folding is mandatory for proteins, and therefore
organisms to properly function.
- Improper protein structure known as the protein folding
problem can result in many neurodegenerative
diseases.
- Protein folding occurs so rapidly that it is not possible to
predict the folding patterns from their sequence of amino
acids.

CHAPERONES
-

Usually, proteins fold into their most stable state spontaneously and
correctly.

When they do require help folding, other proteins called chaperones


come into play.

Chaperones are ubiquitous and induced by stress.

Reduction in intracellular level of chaperones causes the number of


misfolded proteins to increase.

Possible relationship between toxicity in neurodegenerative


disorders and an imbalance between normal chaperone protein
capacity and the production of wrongly-folded proteins.

The more chaperones present, results in a better suppression of


neurotoxicity caused by protein misfolding.

Along with pharmacological chaperones, they have been found to


reduce the severity of many neurological disorders and several other
protein-misfolding diseases.

HEAT SHOCK PROTEINS


- Heat shock proteins (HSPs) are molecular chaperones
which play an extremely important role in the quality
control and folding of proteins. When heat shock
proteins are overly-expressed, it has been noticed that
the number and size of inclusions and accumulation of
disease-causing proteins is drastically reduced.
- These findings bring on the possibility of heat shock
protein therapy for neurodegenerative diseases

DENATURATION AND HUMAN DISORDERS


Proteins misfolding and faulty chaperones are linked to:

- Alzheimers disease
- Cystic fibrosis
- Parkinsons disease
- Huntingtons disease
- CreutzfeldtJakob disease
- Gauchers disease
- and many other degenerative and neurodegenerative
disorders

HALLMARK OF NEURODEGENERATIVE DISORDERS


- Accumulations and inclusions of disease-causing
proteins are the hallmark of neurodegenerative
disorders.
- These inclusions of disease-causing proteins combine
with numerous components of molecular chaperone
pathways and ubiquitin-proteasome, raising the
possibility that misfolding along with altered
degradation of mutant proteins might be responsible for
the pathogenesis of neurodegenerative diseases.

PROTEIN AGGREGATES
Structural changes in proteins can lead to masses of aggregates,
which sometimes result in neurotoxicity and the death of cells.
Misfolded/aggregated proteins called prions become neurotoxic
and are also involved in human disorders or diseases.
Transmissible spongiform encephalopathies (TSEs) are fatal brain
diseases, which are associated with misfolded proteins.
TSEs are thought to be the result of prions causing other similar
proteins to change shape as well.
Mad cow disease is an example of a TSE.
Many p53-mediated cancers are also the result of protein
misfolding.
Mutations in proteins that function as major regulators of growth
and differentiation may cause cancers and other proteinmisfolding disorders.

MAJOR AND MINOR MUTATIONS


Most protein-misfolding disorders are caused by an error in folding which
occurred due to a detrimental mutation in the polypeptide.
Loss of function, as seen in cystic fibrosis is one damaging effect of a
misfolded protein. In cystic fibrosis, the mutations are so severe that they
render the protein biologically inactive.
Other mutations are considered to be minor, because only partial loss of
activity is seen in the resulting protein.
Despite the partial biological activity, of these protein mutants, they are not
delivered to their proper location inside or outside the cell.
This abnormal protein trafficking is observed in a1-antitrypsin deficiency

AMYLOIDS
Frequently, protein misfolding can cause the formation of a harmful
amyloid.
Amyloids are formed when aggregates of proteins are transformed into
a great number of highly insoluble hydrogen bonds within a fibrillar
structure.
Plaque-like structures form from the accumulation of these amyloids.
This gain of function is another devastating effect of improper folding
of a proteins structure, and can be observed in Alzheimer disease,
Parkinsons disease and Huntingtons disease.
These amyloid-related neurodegenerative diseases are often
accompanied by the appearance of a toxic function

AMYLOIDS

PROTEIN IS ESSENTIAL TO LIFE


Obviously, protein structure is extremely important. The function of
each and every cell depends on the shape and structure of protein.
The fact that there are countless combinations of amino acids
possible, but that only one shape is functional for each protein. The
denaturing of proteins by conditions such as high temperatures,
alkalosis, acidosis, osmotic shock, a pH that is too high or too low,
and oxidative stress, shows just how easy it is for one small
environmental change to cause a disorder in humans. When
denaturation is reversible, the fate of a human can be saved. Because
the protein can spontaneously refold into its original functional state.
If the denaturation is not reversible, however, the human could
develop a harmful disorder.

CONCLUSION
Hopefully, research will continue and eventually
we will be able to completely understand the
role of protein structure in human disorders.
For now, just knowing that it is important, is a
great starting point for future research. A small
error in the improper folding of proteins can be
lethal. Down the road, it would be incredible to
see chaperone protein therapy for
neurodegenerative disorders and the like.