Intestinal mucin is a chaperone of multivalent copper

Area of Science:

• Mucosal biology
• Glycoprotein structure-function
• Trace metal metabolism

Background:

• Mucus is vital for protecting epithelial surfaces in the digestive and respiratory tracts.
• Understanding mucus barrier function is hindered by a lack of high-resolution mucin structural data.
• Mucins are large, secreted glycoproteins forming the gel-like mucus matrix.

Purpose of the Study:

• To elucidate the molecular mechanisms of mucus barrier function.
• To discover novel roles of mucins beyond physical protection.
• To investigate the interaction of mucins with essential trace metals like copper.

Main Methods:

• Determination of high-resolution mucin structures.
• Biochemical analysis of copper binding sites within mucins.
• Cellular assays to assess copper toxicity and uptake.

Main Results:

• Structural determination of intestinal mucin MUC2 revealed two distinct copper binding sites (Cu2+ and Cu1+).
• MUC2 prevents copper toxicity by inhibiting futile redox cycling and antioxidant depletion.
• Mucins facilitate cellular uptake of copper despite managing its toxicity.

Conclusions:

• Mucins act as extracellular copper chaperones, managing copper homeostasis.
• Molecular structure of mucins is key to understanding their protective functions.
• Mucins play a critical, previously unrecognized role in regulating essential trace metals at mucosal surfaces.