- Misfolding (altered structure) of proteins and protein aggregation
responsible for many diseases.
- In prion diseases, these misfolded protein aggregates are
functional i.e. self-replicate, and move from cell to cell causing
- Misfolded protein models explain how altered protein structure
might also have important functional implications, critical for
study of protein models can offer insights into how altered protein structure can give rise to
new functions, some of which may be crucial and might give a better
understanding of how organisms evolved over the ages, according to a study
conducted by scientists at Emory University and Georgia Tech.
from diseases caused by misfolding of proteins such as prion diseases ( rare
neurodegenerative diseases caused by a type of protein which triggers the
normal proteins in the brain), Biophysics scientists have used protein models
to explain how alterations in the structure of proteins might
- Explain creation and sustenance of life to keep in tune with the
changing environment, a factor critical in the evolution of species over
- Help to determine if and whether controlling the process of protein
folding and aggregation could one day prevent diseases caused by
Based on their work, the research team published two papers
‘Understanding ways to control or direct protein misfolding could help prevent disease and open up newer vistas in biomolecular engineering.’
According to David Lynn lead author in
the study, "In the first paper we showed that you can create tension
between a chemical and physical system to give rise to more complex systems.
And in the second paper, we showed that these complex systems can have
remarkable and unexpected functions," He adds that
the idea for their research was inspired by the existing understanding of
protein misfolding diseases such as prion disease.
Methods of the Study
To test their hypothesis, the scientists
generated a chemical system of peptides and coupled it to a physical system
alteration in the structure or other words misfolding of proteins.
This combination ultimately led to gradual self-driven progressive
changes in structure induced by the changing environment
These protein polymers can fold into a
seemingly endless array of forms, and sometimes behave like origami, Lynn
explains. "They can stack into
assemblies that carry new functions
, like prions that move from
cell-to-cell, causing disease."
Thus the protein models in the study
inspired by the protein misfolding disease show how altered protein structure
can bring about newer and useful functions as well which is critical for the
phylogenetic evolution of species.
of Beneficial Protein Aggregates in Various Organisms
Although protein misfolding and
aggregation is typically associated with disease, there are many instances in
nature where these protein aggregates
have beneficial purposes from a functional point of view
. Some of these include
- Escherichia coli and other
Enterobacteriaceae employ the rigid structure of amyloid aggregates to
form fibrillar extracellular aggregates that promote bacterial adhesion,
biofilm development and host invasion.
- In higher organisms such as the
spidroin, amyloid aggregates, provide give spider silk a steel-like
- Instances of functional amyloid
aggregates have also been described in humans such as the amyloids of
Pmel17 serving as a template for formation of melanin in mammalian
- An interesting example is the
storage of peptide and protein hormones in the form of amyloid fibrils by
the secretory granules in the pituitary gland.
- It has been postulated that almost
all organisms may have used the toxic properties associated with protein
aggregates to their advantage and developed defensive tools against
Protein Misfolding and Aggregates in
Many neurodegenerative diseases such as Alzheimer's
and various prion and amyloid
diseases are now known to be caused by protein misfolding or by aggregation of
intermediate conformational states, with a tendency
for misfolding enhanced by certain mutations
the human eye have also been shown to be caused by an accumulation of misfolded proteins and
associated with mutations that increase the risk of misfolding.
Cellular Mechanisms to Prevent Misfolding and
Cells have evolved mechanisms to prevent
misfolding and aggregation of proteins, thereby preventing or reducing the occurrence
of disease. Some of these include
- Strict maintenance of protein
concentration within the cell as this is shown to influence the formation
of protein aggregates.
- Mechanisms such as chaperones that
aid the protein folding process and reduce the chances of misfolding. They
also reduce interactions of peptides with other molecules that may lead to
aggregation and increase protein solubility within the cell.
- Creation and maintenance of an
optimal environment to ensure correct folding of the proteins.
More research and insight into these
physiological mechanisms could one day prevent such diseases.
Role of Biophysics in the Health Sciences
Biological evolution employs genetic
alterations or mutations as its basic working material. The current study of molecular evolution
employs large amounts of protein sequence data, but only a relatively small
body of protein structural data.
- Research often fails to consider the
impact of the structure and binding properties of peptides and amino acids
in limiting the scope for evolution. Towards this end, a number of
scientists from the biophysics community have recently called for a
stronger interaction between the fields of Biophysics and Evolutionary
Biology to understand the process of evolution better.
- Gaining better insight into protein
structure and its impact on protein function can help in developing newer
treatments or even prevention of protein misfolding diseases.
In conclusion, though there is a long way
to go before definitive answers might be obtained, a step in the right
direction has nevertheless been made to uncover the mysteries of evolution and
- Neutral theory of molecular evolution - (https://en.wikipedia.org/wiki/Neutral_theory_of_molecular_evolution)
- Biophysics of protein evolution and evolutionary protein biophysics - (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4191086/)
- Biophysical models of protein evolution: Understanding the patterns of evolutionary sequence divergence - (http://biorxiv.org/content/biorxiv/early/2016/08/30/072223.full.pdf)