Mechanisms that create non selective pores in cellular membranes have been a defence and attack tool used by a wide range organisms form time immemorial. Cytotoxic proteins with this capacity are produced by bacteria, amoebas, fungi, anemone, and vertebrates (as part of their immune system) as well as in the poison of some arthropods and snakes.
Although, the proteins that are capable of producing such destabilising pores in the cellular membrane of organisms can be very different in terms of the sequence of amino acids that forms them, they all create permeabilizing structures that increase the overall permeability of the semi-permeable cellular membrane allowing for a passive flow of ions and other small substances. Up to now there was no evidence of such properties from viral origin.
The research group led by Professor Luis Carrasco from the Centro de Biología Molecular Severo Ochoa (UAM-CSIC) in Madrid has been studying the mechanism of late permeabilization caused by different viruses and among them the poliomyelitis virus. In the late stages of the infection produced by most animal viruses, a permeabilization phenomenon takes place in the cellular membranes that is very important to ensure an easier release of the new viral particles to the exterior of the cell.
In the last few years, different studies have demonstrated that the individual expression of certain viral genes could reproduce this process in several cellular systems. It was then that the name “viroporin” was established for the viral proteins that shared some structural properties in addition to the permeabilizing effect on the membranes.
The poliovirus protein 2B, known as the causal agent of poliomyelitis, as well as its precursor (2BC), are viroporins that increase the permeability of bacterial and mammalian cell membranes. In previous studies, with the application of biophysical techniques, it was proven that the addition of the purified protein 2B induces permeabilization in artificial membranes (liposomes) to substances of a low molecular weight, fitting in with this phenomenon in cells.
All these demonstrate that the permeabilization mechanism of viroporins could be similar to that of some toxins that create pores. In the recently published Journal of Molecular Biology, the research group managed by Professor Carrasco in collaboration with Dr. Nieva and Dr. Sánchez-Martínez from the Universidad del País Vasco as well as the research team directed by Dr. Rispoli from the Università di Ferrara (Italy), present proof of the intrinsic capabilities of viroporin 2B to create stable pores with set dimensions in the cellular membranes. The contributing researchers have determined the region of protein 2B that constitutes the pore and have investigated its characteristics. To do this they used chemical synthesis to obtain short fragments (peptides) that would cover the different areas of the complete protein and out of all the sampled peptides indentified that only one helical peptide exhibited permeabilizing activity in cells when added in a very low concentration. This peptide can introduce itself into both the cellular membrane as well as the liposomes, and only allowed the flow of very small compounds and not macromolecules, which enabled the approximation of the inner diameter of the pore.
Finally, the researchers had managed to confirm in physiological conditions, the presence of the pores formed by the peptide derived from the viroporin 2B. A new technique developed by the Italian researchers, using a series of electro physiological methods, detects the formation of ion channels only a few seconds after applying the peptide directly to an individual cell. Therefore, the viroporin 2B of the poliomyelitis virus constitutes a new class of pore forming protein that are synthesised during infection and act like toxins inside the infected cells.
The study of viroporins and the detection of the regions responsible for their permeabilizing function open up an interesting field of investigation with several future applications such as a base for new cytotoxic drugs. In addition, these studies set the base for the design of new peptides that would interfere with the pore formation and antiviral compounds capable of inhibiting the function of viroporins in the infection process.
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