Dynamics of Various Phospholipase C-B Complexes

Abstract

The epithelial single-pass transmembrane glycoprotein Mucin 1 (MUC1) is a main constituent of mucus and has roles in cell signaling and differentiation. In addition, overexpression and subsequent homodimerization of the C-terminal subunit of MUC1 has been implicated in the progression of many cancers, particularly breast cancer. Recent experiments have shown that strong dimerization is dependent on the formation of disulfide bonds between two cysteine residues in the juxtamembrane region, but weak dimers can also be formed without them. Certain mutations in the TMD can also partially disrupt the strength of the dimer. This suggests that protein-protein or protein-lipid interactions are also mediating dimer formation. However, the transmembrane domain of MUC1-C doesn't appear to contain common oligomerization motifs such as the Sm-X 3 -Sm sequence found in glycophorin A and many receptor tyrosine kinases. Understanding the physical mechanisms by which MUC1-C dimerizes within the surrounding plasma membrane environment will help in creating drug targets, as well as generating a more comprehensive model of protein-lipid interactions. To investigate this, atomistic replica exchange molecular dynamics simulations are being used to find stable conformations of wild-type and mutant MUC1 TMDs.