Abstract
Determining the principles governing lipid-protein interactions, specifically those in single-pass transmembrane protein dimerization, are fundamental problems in the field of membrane biophysics. Mucin-1 (MUC1), a mucus constituent found on the apical side of epithelial cells, typically acts as a barrier against pathogens but has also been identified as an oncogene. When overexpressed, the C-terminal subunit of MUC1 is known to homodimerize and undergo nuclear translocation as well as interact with growth factors and other kinases in signaling cascades to promote metastasis, inflammation, and drug resistance. MUC1 homodimerization in the membrane occurs due to a pair of disulfide bonds formed between two adjacent monomers. Strong dimerization affinity in bacterial membranes comparable to glycophorin A has been observed experimentally, and weak affinity is seen even without the cytosolic membrane-proximal cysteine residues. Several mutations in the TMD, most notably Ala-1180-Leu, also affect dimerization. All-atom molecular dynamics simulations of the transmembrane and juxtamembrane domains of MUC1 have been used to better quantify the dimer structure and binding energetics. Umbrella sampling and free energy perturbation methods were used to generate potential of mean force (PMF) curves, which were then compared to experimental assay activity.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.