Intestinal Mucin Is a Chaperone of Multivalent Copper

Mucus protects the epithelial cells of the digestive and respiratory tracts from pathogens
and other hazards. Progress in determining the molecular mechanisms of mucus barrier
function has been limited by the lack of high-resolution structural information on mucins,
the giant, secreted, gel-forming glycoproteins that are the major constituents of mucus.
Here we report how mucin structures we determined enabled the discovery of an
unanticipated protective role of mucus: managing the toxic transition metal copper. Using
two juxtaposed copper binding sites, one for Cu²⁺ and the other for Cu¹⁺, the intestinal
mucin, MUC2, prevents copper toxicity by blocking futile redox cycling and the
squandering of dietary antioxidants, while nevertheless permitting uptake of this important
trace metal into cells. These findings emphasize the value of molecular structure in
uncovering new aspects of mucosal biology, while introducing mucins, produced in
massive quantities to guard extensive mucosal surfaces, as extracellular copper
chaperones.