title: Molecular insights into dimerization inhibition of c-Maf transcription factor.
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.
authors.affiliation: DISFARM - Section of General and Organic Chemistry "A. Marchesini", University of Milan, Via Venezian 21, 20133 Milan, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Pellegrino
authors.affiliation: Department of Neurosciences, University of Parma, Parco Area delle Scienze 23/A, 43124 Parma, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Ronda
authors.affiliation: DISFARM - Section of General and Organic Chemistry "A. Marchesini", University of Milan, Via Venezian 21, 20133 Milan, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Annoni
authors.affiliation: DISFARM - Section of General and Organic Chemistry "A. Marchesini", University of Milan, Via Venezian 21, 20133 Milan, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Contini
authors.affiliation: DISFARM - Section of General and Organic Chemistry "A. Marchesini", University of Milan, Via Venezian 21, 20133 Milan, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Erba
authors.affiliation: DISFARM - Section of General and Organic Chemistry "A. Marchesini", University of Milan, Via Venezian 21, 20133 Milan, Italy.
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Gelmi
authors.affiliation: Department of Neurosciences, University of Parma, Parco Area delle Scienze 23/A, 43124 Parma, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Piano
authors.affiliation: Department of Pharmacy, University of Parma, Parco Area delle Scienze 23/A, 43124 Parma, Italy; SITEIA.PARMA Interdepartmental Center, University of Parma, Parco Area delle Scienze 181/A, 43124 Parma, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Paredi
authors.affiliation: Department of Pharmacy, University of Parma, Parco Area delle Scienze 23/A, 43124 Parma, Italy; National Institute of Biostructures and Biosystems, Viale Medaglie d'Oro 305, 00136 Rome, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Mozzarelli
authors.affiliation: Department of Neurosciences, University of Parma, Parco Area delle Scienze 23/A, 43124 Parma, Italy; National Institute of Biostructures and Biosystems, Viale Medaglie d'Oro 305, 00136 Rome, Italy. Electronic address: stefano.bettati@unipr.it.
authors.forename: Stefano
authors.initials: S
authors.lastname: Bettati
keywords: Dimerization inhibitor; Intrinsically disordered protein; Maf transcription factor; Molecular dynamics; Multiple myeloma; Solid phase peptide synthesis