The defense mechanisms that human cells have against viruses such as monkeypox, herpes simplex, and human papillomavirus – all double-stranded DNA viruses – rely on proteins that patrol the cell as sensors for viral DNA. This is a type of cellular defense that was discovered almost a decade ago and is still little studied. When the sensor proteins detect viral DNA, they bind to it, and then an alarm goes off: the cell activates its defenses. But viruses, as in the arms race, also have proteins capable of blocking these cellular alarm systems.
One of the proteins that alert cells to the presence of DNA viruses is a protein complex called ku. scientist from CNIO and from sussex university has now successfully characterized its three-dimensional structure at the atomic level, coupled with a viral protein capable of blocking this complex. These findings, published in the journal Nature Communications, This will increase the response to this infection.
Researchers have worked with the Vaccinia virus (used in the development of the smallpox vaccine and belonging to the poxvirus family). Two proteins of this virus, called C4 and C16, bind to Ku and block its action, deactivating the cellular immune response. Knowing the shape of these proteins, their three-dimensional structure, helps to understand how they do this.
Protein as a plug to deactivate the Ku ring
Ku is ring-shaped, with a central hole through which it inserts itself into DNA. Researchers have found that two viral proteins act as plugs that plug the gap, blocking Ku’s ability to recognize viral DNA (see graphic animation).
Researchers from the group CNIO of Macromolecular Complexes in Response to DNA Damage, led by Óscar Llorca, have succeeded in obtaining the structure of the C16-Ku complex via cryoelectron microscopy, a technique that allows visualizing interactions between viral proteins and human proteins.
In this way, the authors of the work were able to identify which part of the viral protein caused Ku blockade. “Ku heterodimers form a kind of ring that is connected to DNA. The viral protein acts as a kind of stopper for this ring, thereby blocking the binding of Ku to the viral DNA”, explains Óscar Llorca.
This activity is carried out in collaboration with groups University of Sussex (England) led by researcher Laurence H. Pearl, who has confirmed that the mechanism of action of the C4 protein is very similar to that of C16.
Block Ku from helping the tumor cells
Ku complexes are also present in the nucleus of cells, but their role there is not to warn of viruses but to repair our own genetic material when it is damaged.
Llorca’s group studied the role of a ku-like protein complex in cancer, which is involved in the repair of double-stranded DNA. When these repair mechanisms act on tumor cells, they favor their survival, and thus become cancerous. Now it is known, thanks to a new work, how the virus blocks my action, its role in DNA damage repair can be learned to change from tumor cells.
«The idea for this study arose because if in a treatment to produce damage to the DNA of tumor cells we can block Ku function during the DNA repair process, in a similar way to viruses, the treatment will still be more effective. ,” said Ángel Rivera-Calzada, one of the study’s lead authors.
In this way, one of the next steps will be to evaluate whether mimicking the mechanism of viral proteins to block Ku will serve to develop strategies that will amplify the effects of cancer treatment.
Knowing the shape of these proteins, their three-dimensional structure, helps to understand how they do this.
“Of all the viral proteins, it is the few of the few amino acids that work by blocking the action of Ku,” says Rivera-Calzada. The first step is to ensure that the tiny fragments are produced in a laboratory Yescapable of blocking DNA recognition damaged. For this purpose, the authors of the paper trust to collaborate with CNIO experts in this type of strategy.
Deepen its role against viral infections
In addition, the information obtained can help develop strategies to fight infection caused by the virus. Comparison protein sequences of the C4 and C16 homologs in other viruses of the family, researchers have been able to observe that the regions involved in Ku inactivation are highly conserved. Among these viruses, for example the smallpox virus or monkeypox virus, which has recently been in the news because of the emergence of many cases in various European countries. To this end, the researchers propose future collaboration with a specialist group in the field of virology.
“Internet trailblazer. Troublemaker. Passionate alcohol lover. Beer advocate. Zombie ninja.”
