Computational analysis of prodomain cysteines in human TGF-beta proteins reveals frequent loss of disulfide-dependent regulation in tumors

The functionally diverse members of the human Transforming Growth Factor-beta (TGF-beta) family are tightly regulated. TGF-beta regulation includes 2 disulfide-dependent mechanisms-dimerization and partner protein binding. The specific cysteines participating in these regulatory mechanisms are known in just 3 of the 33 human TGF-beta proteins. Human prodomain alignments revealed that 24 TGF-beta prodomains contain conserved cysteines in 2 highly exposed locations. There are 3 in the region of the beta 8 helix that mediates dimerization near the prodomain carboxy terminus. There are 2 in the Association region that mediates partner protein binding near the prodomain amino terminus. The alignments predict the specific cysteines contributing to disulfide-dependent regulation of 72% of human TGF-beta proteins. Database mining then identified 9 conserved prodomain cysteine mutations and their disease phenotypes in 7 TGF-beta proteins. Three common adenoma phenotypes for prodomain cysteine mutations suggested 7 new regulatory heterodimer pairs. Two common adenoma phenotypes for prodomain and binding partner cysteine mutations revealed 17 new regulatory interactions. Overall, the analysis of human TGF-beta prodomains suggests a significantly expanded scope of disulfide-dependent regulation by heterodimerization and partner protein binding; regulation that is often lost in tumors.