Investigating the Role of Transmembrane Domain Cysteine Residues in the Organization of TNF Receptors

Abstract

We recently showed that disulfide bond formation via cysteine residues in the transmembrane (TM) domains of the long isoform of Death Receptor 5 play a significant role in receptor homodimerization and activation. This is significant because the dominant paradigm in TNF Receptor signaling had been that receptor trimers, not dimers, are the signaling competent oligomeric state. Here, we surveyed the full TNF Receptor superfamily and found that potential TM domain disulfide bonds exist in approximately one third of the superfamily members. To investigate the broader importance of these cysteine residues and the potential for disulfide bond formation in the TNF Receptor superfamily, we studied Fas and TNF-Receptor 1 in cells. We also performed computational calculations (potential of mean force) to explore the thermodynamics of conformational changes of disulfide-bonded TM domain dimers. Additionally, we performed a bioinformatics study on transmembrane domains to further investigate the prevalence of TM domain cysteine residues and potential disulfide bonded TM dimers.