Protein Structure and Molecular Evolution

Highlights:

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 neurodegeneration.
Misfolded protein models explain how altered protein structure might also have important functional implications, critical for phylogenetic evolution.

Biophysical 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.

Reason for Study

Taking a cue 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 time.
Help to determine if and whether controlling the process of protein folding and aggregation could one day prevent diseases caused by misfolding.

Based on their work, the research team published two papers in Nature Chemistry.

What Leads to Prion Disease Described
By studying prion disease in the retina, researchers were able to determine the time lag between stages of the disease process.

‘Understanding ways to control or direct protein misfolding could help prevent disease and open up newer vistas in biomolecular engineering.’

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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 involving an 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.

New Clues About Parkinson's Disease and Other 'Synucleinopathies'
Parkinson's disease and other synucleinopathies are known to be linked to the misfolding of alpha-synuclein protein in neurons.

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.

Fruit Fly Neurons Hold Key to Molecular Causes of Mental Diseases
A neuron is a cell that processes and transmits information through electrical and chemical signals in the brain.

Examples 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 strength.
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 melanocytes.
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 pathogenic micro-organisms.

Protein Misfolding and Aggregates in Human Disease

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. Cataracts in 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.

Chemical Chaperone may Be a Treatment Option for Neurological Disorders
Researchers at Washington University School of Medicine in St. Louis have come up with a new treatment method for Niemann-Pick disease, a rare, deadly neurodegenerative disorder.

Cellular Mechanisms to Prevent Misfolding and Disease Causation

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 disease.

References:

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)

Source-Medindia