Cysteine‐Mediated Dimerization of the Transmembrane Domain of Mucin 16

Abstract

Mucins are proteins in the epithelial tissue that produce mucus barriers to provide moisture and also prevent harmful, foreign material from entering the cell. These proteins are heavily glycosylated, and can be secreted to the extracellular space or be embedded in the plasma membrane. The overexpression of transmembrane mucins have been correlated with the development of cancerous growths. For example, the transmembrane mucins mucin 1 (MUC1) and mucin 16 (MUC16) have been associated with breast and ovarian cancer, respectively.The role of MUC1 in tumor progression has been extensively studied. Dimerization of MUC1 leads to its trafficking to the nucleus where it can alter the expression of genes that regulate cell growth. The cysteine‐glutamine‐cysteine (CQC) motif in the cytosolic juxtamembrane domain of MUC1 is the main driving force of this dimerization, primarily through the formation of disulfide bonds. Contrary to MUC1, there is not much information regarding the possible intracellular role of MUC16 in tumor formation and progression. Similar to MUC1, MUC16 also has two cysteine residues at or near the juxtamembrane domain. Furthermore, recent studies have observed the presence of MUC16 in the nucleus. Thus, we hypothesized that there may be a similarity in the mechanism of trafficking of MUC1 with that of MUC16.We are using the ToxR activity assay to assess the dimerization of the transmembrane domains of MUC1 and MUC16 with and without the juxtamembrane cysteines. Our preliminary results show that, in the presence of the cysteine residues, the transmembrane domain of MUC16 dimerizes as strongly as that of MUC1. Our results also show that the strength of dimerization, in both MUC1 and MUC16 are associated with the formation of disulfide bonds. These results suggest a possible mechanism of MUC16 nuclear trafficking, similar to that of MUC1, involving cysteine‐mediated dimerization.Support or Funding InformationNicholas & Susan Nicholaides Research Fellowship, and the SJU Summer Scholars ProgramThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.