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

Samantha M. Daly, Ashley Peraza, Stuart J. Newfeld

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

The functionally diverse members of the human Transforming Growth Factor-β (TGF-β) family are tightly regulated. TGF-β 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-β proteins. Human prodomain alignments revealed that 24 TGF-β prodomains contain conserved cysteines in 2 highly exposed locations. There are 3 in the region of the b8 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-β proteins. Database mining then identified 9 conserved prodomain cysteine mutations and their disease phenotypes in 7 TGF-β 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-β prodomains suggests a significantly expanded scope of disulfide-dependent regulation by heterodimerization and partner protein binding; regulation that is often lost in tumors.

Original languageEnglish (US)
Article numberjkac271
JournalG3: Genes, Genomes, Genetics
Volume12
Issue number12
DOIs
StatePublished - Dec 2022

Keywords

  • Fibrillin
  • Genome Data Commons
  • LTBP
  • adenocarcinoma

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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