Challenges in Targeting a Basic Helix–Loop–Helix Transcription Factor with Hydrocarbon-Stapled Peptides
Citations Over TimeTop 16% of 2016 papers
Abstract
Basic helix-loop-helix (bHLH) transcription factors play critical roles in organism development and disease by regulating cell proliferation and differentiation. Transcriptional activity, whether by bHLH homo- or heterodimerization, is dependent on protein-protein and protein-DNA interactions mediated by α-helices. Thus, α-helical decoys have been proposed as potential targeted therapies for pathologic bHLH transcription. Here, we developed a library of stabilized α-helices of OLIG2 (SAH-OLIG2) to test the capacity of hydrocarbon-stapled peptides to disrupt OLIG2 homodimerization, which drives the development and chemoresistance of glioblastoma multiforme, one of the deadliest forms of human brain cancer. Although stapling successfully reinforced the α-helical structure of bHLH constructs of varying length, sequence-specific dissociation of OLIG2 dimers from DNA was not achieved. Re-evaluation of the binding determinants for OLIG2 self-association and stability revealed an unanticipated role of the C-terminal domain. These data highlight potential pitfalls in peptide-based targeting of bHLH transcription factors given the liabilities of their positively charged amino acid sequences and multifactorial binding determinants.
Related Papers
- → Artificial ligand binding within the HIF2α PAS-B domain of the HIF2 transcription factor(2009)290 cited
- → Homodimeric and Heterodimeric Interactions among Vertebrate Basic Helix–Loop–Helix Transcription Factors(2021)38 cited
- → Muscle basic helix-loop-helix proteins and the regulation of myogenesis(1992)69 cited
- → Transriptional regulation of the mouse IP[3]R1 gene by the CNS-related basic helix-loop-helix factor; NDRF(2000)
- An Id-related helix-loop-helix protein encoded by a growth(2016)