Elucidating The Structural Consequences Of Cqc-Mediated Dimerization Of Muc1

Mucin 1 (MUC1) is a highly glycosylated single pass membrane protein that serves as a selective barrier against pathogens and engages in signal transduction influencing cellular growth and differentiation. Overexpression of mucins have been linked to 80‐90% of all human solid tissue cancers. Constitutive homodimerization, as a result of overexpression, leads to the formation of complexes with growth factor receptors and targeting to the nucleus, where MUC1 interacts with effector proteins regulating gene expression. Recent studies have shown that the MUC1 cytosolic membrane proximal CQC motif promotes dimerization under oxidizing conditions, suggesting that the motif may act as a redox switch in response to changes of oxidant levels. Preliminary studies have shown that the transmembrane domain (TMD) of MUC1 lacking the CQC motif form weak dimers, confirming their contribution to dimerization. Also, results show that TMDs containing the CQC in an oxidizing environment exhibit increased dimerization, further enforcing the role of the motif acts as a redox switch. Using the ToxR dimerization assay, the effects of single amino acid substitutions in TMDs with the CQC motif and TMDs with the CQC‐>AQA motif are being measured. Our goal is to determine (1) whether certain amino acids in the TMD play a key role in forming MUC1 homodimers, and (2) whether the CQC motif induces a structural change when it functions as a redox switch. These conclusions will contribute to our understanding of MUC1 dimerization and provide insights for the development of novel therapeutic strategies.