Function Of Critical Immune-Surveillance Protein In Humans


Scientists have defined the structure and key features of a human immune-surveillance protein that guards against cancer and bacterial and viral infections. The identification of two human-specific variations in the protein closes a critical knowledge gap in immunology and cancer biology. The study was published in Cell.

The human body is built for survival. Each one of its cells is closely guarded by a set of immune proteins armed with nearly foolproof radars that detect foreign or damaged DNA. One of the cells' most critical sentinels is a "first responder" protein known as cGAS, which senses the presence of foreign and cancerous DNA and initiates a signaling cascade that triggers the body's defenses.

Human cGAS

The structure and mechanism of action of human cGAS have been critical missing pieces in immunology and cancer biology. Importantly, the findings can inform the design of small-molecule drugs tailored to the unique structural features of the human protein, an advance that promises to boost the precision cGAS-modulating drugs that are currently in development as cancer therapies.

Correctly, the research shows that human cGAS harbors mutations that make it exquisitely sensitive to long lengths of DNA but render it "blind" or "insensitive" to short DNA fragments. Human cGAS is a highly discriminating protein that has evolved enhanced specificity toward DNA.


Taking advantage of a cholera enzyme that shares similarities with cGAS, the scientists were able to recreate the function of both human and mouse cGAS in the bacterium. In a series of experiments, the scientists observed activation patterns between the different types of cGAS, progressively narrowing down the key differences that accounted for differential DNA activation among the three.

The experiments revealed that out of the 116 amino acids that differ in human and mouse cGAS, only two accounted for the altered function of human cGAS. Indeed, human cGAS was capable of recognizing long DNA with great precision but it ignored short DNA fragments. 

These two tiny amino acids make a world of difference. They allow the human protein to be highly selective and respond only to long DNA while ignoring short DNA, essentially rendering the human protein more tolerant of DNA present in the cytosol of the cell.

Amino Acids

The two amino acids responsible for sensing long DNA and tolerating short DNA are found solely in humans and nonhuman primates, such as gorillas, chimps and bonobos.

X-ray crystallography

To do so, they used a visualization technique known as X-ray crystallography, which reveals the molecular architecture of protein crystals based on a pattern of scattered X-ray beams.  Profiling the structure of cGAS "in action" revealed the precise molecular variations that allowed it to selectively bind to long DNA while ignoring short DNA.

Understanding what makes the structure and function of human cGAS different from those in other species was the missing piece. Now that they have it, they can really start designing drugs that work in humans.