Data di Pubblicazione:
2014
Citazione:
Molecular insights into dimerization inhibition of c-Maf transcription factor / S. Pellegrino, L. Ronda, C. Annoni, A. Contini, E. Erba, M.L. Gelmi, R. Piano, G. Paredi, A. Mozzarelli, S. Bettati. - In: BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS. - ISSN 1570-9639. - 1844:12(2014 Dec), pp. 2108-2115. [10.1016/j.bbapap.2014.09.003]
Abstract:
The Maf protein family belongs to the activator protein 1 (AP-1) superfamily of transcription factors that bind specific DNA target sequences through a basic region and exploit a leucine zipper (LZ) motif for protein-protein interactions leading to homo- or hetero-dimerization. Mafs unique DNA-binding domain contains a highly conserved extended homology region (EHR) that allows to recognize longer DNA sequences than other basic leucine zipper (bZIP) transcription factors. Inspired by the fact that overexpression of Mafs is observed in about 50% of cases of multiple myeloma, a hematological malignant disorder, we undertook a peptide inhibitor approach. The LZ domain of c-Maf, one of large Mafs, was produced by solid phase peptide synthesis. We characterized its secondary structure and dimerization properties, and found that dimerization and folding events are strictly coupled. Moreover, potential peptidic c-Maf dimerization inhibitors were computationally designed and synthesized. These compounds were demonstrated by circular dichroism (CD) spectroscopy and MALDI-TOF mass spectrometry to bind to c-Maf LZ monomers, to drive folding of their partially disordered structure and to efficiently compete with dimerization, suggesting a way for interfering with the function of c-Maf and, more generally, of intrinsically disordered proteins, till now considered undruggable targets.
Tipologia IRIS:
01 - Articolo su periodico
Keywords:
Dimerization inhibitor ; Intrinsically disordered protein ; Maf transcription factor ; Molecular dynamics ; Multiple myeloma ; Solid phase peptide synthesis ; Biochemistry ; Biophysics ; Analytical Chemistry ; Molecular Biology
Elenco autori:
S. Pellegrino, L. Ronda, C. Annoni, A. Contini, E. Erba, M.L. Gelmi, R. Piano, G. Paredi, A. Mozzarelli, S. Bettati
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