Pierre Coulombe

The X Factor

By Maryalice Yakutchik • Photo by Chris Hartlove

If the skin you’re in is in good shape, you may need to thank the X.

A surprising X-shaped discovery made by Bloomberg School scientists not only reveals the core chemical architecture of nanofibers inside of skin cells but also may provide new insight about how skin manages to be an effective portal, one that’s both protective and permeable.

“From form follows function,” says Pierre Coulombe, PhD, the E.V. McCollum Professor and Chair of the Department of Biochemistry and Molecular Biology. “We found a form that was unexpected. And now we are in the early stages of revealing a new type of function for these nanofibers.”

His team was shocked to find a specific type of chemical bond called a cystine linkage lurking inside cells.

“Cystine linkages are quite abundant in biological systems, but outside cells, not in them,” Coulombe says.

The particular nanofibers that he studies originate from coiled coils of keratins, which are protein components manufactured by 70 genes. He discovered in 1991 that a mutation in one of these genes causes a disease (epidermolysis bullosa simplex) characterized by skin so fragile that it can be shredded by even minimal friction—the kind caused by well-fitting shoes. In a high-tech search for clues to reveal the mechanism, his team scrutinized the nanofiber’s most basic structural makeup using X-ray crystallography, a sophisticated technique accomplished with the assistance of Daniel Leahy and Min-Sung Kim of the Johns Hopkins School of Medicine.

Focusing on mouse skin, the researchers obtained data to suggest that the X-shaped orientation of keratin nanofibers and the associated cystine linkages concentrate around the cell’s nucleus, which houses the genome.

“This is the first evidence that the size and shape of nuclei may be impacted by a keratin nanofiber network,” says Coulombe, who credits the perseverance of Chang-Hun Lee, a former postdoc and first author of the study published in June in Nature Structural & Molecular Biology.

“Nine out of 10 people would have said the odd discovery of the X shape was an artifact and not bothered trying to pursue it,” he recalls. “But Chang-Hun did bother, and we found a new form that’s leading us to uncover new function.”

The next step for Coulombe’s lab is to use genetic engineering to investigate the consequences of preventing the formation of these cystine linkages and the associated X-shaped orientation of keratin nanofibers in their natural context in the skin.

The big-picture question, ultimately, is how do the sizes and shapes of nuclei—of not only skin cells, but all kinds—affect cellular processes.

“This is an area of biology that’s beginning to get traction,” Coulombe says. “For one thing, it’s going to help us understand how the skin achieves a form that allows it to be an effective interface, fostering a healthy relationship with our environment.”