title: Disclosing the Interaction of Carbonic Anhydrase IX with Cullin-Associated NEDD8-Dissociated Protein 1 by Molecular Modeling and Integrated Binding Measurements.
abstract: Human Carbonic Anhydrase (hCA) IX is a membrane-associated member of the CA enzyme family, involved in solid tumor acidification. This enzyme is a marker of tumor hypoxia and a prognostic factor for several human cancers. In a recent paper, we showed that CA IX interacts with cullin-associated NEDD8-dissociated protein 1 (CAND1), a nuclear protein involved in gene transcription and assembly of SCF ubiquitin ligase complexes. A functional role for this interaction was also identified, since lower CA IX levels were observed in cells with decreased CAND1 expression via shRNA-mediated interference. In this paper, we describe the identification of the structural determinants responsible for the CA IX/CAND1 interaction by means of a multidisciplinary approach, consisting of binding assay measurements, molecular docking, and site-directed mutagenesis. These data open a novel scenario in the design of anticancer drugs targeting CA IX. Indeed, the knowledge of the structural determinants responsible for the CAND1/CA IX interaction provides the molecular basis to design molecules able to destabilize it. Due to the proposed function of CAND1 in stabilizing CA IX, these molecules could represent an efficient tool to lower the amount of CA IX in hypoxic cancer cells, thus limiting its action in survival and the metastatic spread of tumors.
authors.affiliation: Istituto di Biostrutture e Bioimagini, CNR , Naples, Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: Buonanno
authors.affiliation: Istituto di Biostrutture e Bioimagini, CNR , Naples, Italy.
authors.forename: Emma
authors.initials: E
authors.lastname: Langella
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II and CEINGE Biotecnologie Avanzate SCaRL , Naples, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Zambrano
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II and CEINGE Biotecnologie Avanzate SCaRL , Naples, Italy.
authors.forename: Mariangela
authors.initials: M
authors.lastname: Succoio
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II and CEINGE Biotecnologie Avanzate SCaRL , Naples, Italy.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Sasso
authors.affiliation: Istituto di Biostrutture e Bioimagini, CNR , Naples, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Alterio
authors.affiliation: Istituto di Biostrutture e Bioimagini, CNR , Naples, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Di Fiore
authors.affiliation: Istituto di Biostrutture e Bioimagini, CNR , Naples, Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Sandomenico
authors.affiliation: Neurofarba Department, Section of Pharmaceutical and Nutriceutical Sciences, Università degli Studi di Firenze , Sesto Fiorentino, Florence, Italy.
authors.forename: Claudiu T
authors.identifier: 0000-0003-4262-0323
authors.initials: CT
authors.lastname: Supuran
authors.affiliation: Proteomics and Mass Spectrometry Laboratory, ISPAAM, CNR , Naples, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Scaloni
authors.affiliation: Istituto di Biostrutture e Bioimagini, CNR , Naples, Italy.
authors.forename: Simona Maria
authors.initials: SM
authors.lastname: Monti
authors.affiliation: Istituto di Biostrutture e Bioimagini, CNR , Naples, Italy.
authors.forename: Giuseppina
authors.identifier: 0000-0001-9783-5431
authors.initials: G
authors.lastname: De Simone
mesh_terms: D000071231:Carbonic Anhydrase IX / Q000737:chemistry / Q000378:metabolism*; D002257:Carbonic Anhydrase Inhibitors; D006801:Humans; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D016297:Mutagenesis, Site-Directed; D011485:Protein Binding; D055550:Protein Stability; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism*
chemical_list: C486317:CAND1 protein, human; D002257:Carbonic Anhydrase Inhibitors; D014157:Transcription Factors; D000071231:Carbonic Anhydrase IX