Paola Bisignano, Ph.D.

Research Associate Professor

paola.bisignano@vanderbilt.edu
Faculty Appointments
Research Associate Professor of Molecular Physiology & Biophysics
Education
Ph.D., Drug Discovery, Istituto Italiano di Tecnologia, Genoa, Not Specified, ItalyM.S., Cellular and Molecular Biology, Università di Genova, Genoa, ItalyB.S., Biological Sciences, Università di Genova, Genoa, Italy
Research Description
My research focuses on integral membrane proteins, which are essential components of various organisms. These proteins, including ion channels, receptors, and transporters, play crucial roles in fundamental biological processes like nutrient transport, neurotransmitter activity, and cellular signaling. They are also significant targets for therapeutic interventions, with approximately 70% of drugs targeting membrane proteins. While high-resolution structural studies have provided static snapshots of these proteins, they often lack insights into their dynamics and true functionality. To bridge this gap, my research program employs molecular simulation techniques that integrate static structural data with biochemical and functional assays. This approach enables a comprehensive understanding of protein function and guides computational chemistry efforts for drug design.
During my postdoctoral appointment at UCSF, I focused on three critical classes of membrane proteins: solute carrier (SLC) transporters, G-protein coupled receptors (GPCRs), and ciliary ion channels. SLC transporters facilitate the movement of small molecules, GPCRs initiate intracellular signaling in response to external cues, and ciliary GPCRs and ion channels are modulated by ciliary lipids and maintain cellular homeostasis.
During my tenure as a Staff Scientist at Lawrence Livermore Laboratory, I led computational chemistry efforts targeting oncogenic proteins, which expedited the development of a drug candidate for clinical trials. I also continued to collaborate with the Delling lab at UCSF to unravel how sterol binding to ciliary ion channels triggers cell signaling in primary cilia (R01 DK127277).
At Vanderbilt University, my research involves integrating structural modeling from the AlphaFold2 (AF2) artificial intelligence system with enhanced sampling techniques. We also incorporate native mass spectrometry, high-resolution structure, biophysical techniques, and cell-biological assays from the Mchaourab and Carrasco laboratories. Our goal is to understand how conformational changes upon substrate or lipid binding to membrane proteins, such as transporters, ion channels, and receptors, elicit downstream signaling in various cell types, including those involved in cancer, metabolic disorders, and neurological disorders. This interdisciplinary approach enables us to comprehensively investigate the impact of disease mutations on protein function, conformational changes, substrate/drug binding, and their effects on cellular biology.

Research Keywords
Structural Biophysics, Molecular Dynamics, Molecular Modelling, Computational Chemistry, Structure Based Drug Design, Ligand Based Drug Design, Chemoinformatics, Pharmacophore, Membrane proteins
Publications
Eaton C, Avalos L, Liu SJ, Casey-Clyde T, Bisignano P, Lucas CH, Stevenson E, Choudhury A, Vasudevan H, Magill S, Krogan N, Villanueva-Meyer J, Swaney D, Raleigh D. MerlinS13 phosphorylation controls meningioma Wnt signaling and magnetic resonance imaging features. Res Sq. 2023 Mar 3/14/2023; PMID: 36993679, PMCID: PMC10055685, PII: rs.3.rs-2577844, DOI: 10.21203/rs.3.rs-2577844/v1.

Tolani B, Celli A, Yao Y, Tan YZ, Fetter R, Liem CR, de Smith AJ, Vasanthakumar T, Bisignano P, Cotton AD, Seiple IB, Rubinstein JL, Jost M, Weissman JS. Ras-mutant cancers are sensitive to small molecule inhibition of V-type ATPases in mice. Nat Biotechnol [print-electronic]. 2022 Dec; 40(12): 1834-44. PMID: 35879364, PMCID: PMC9750872, PII: 10.1038/s41587-022-01386-z, DOI: 10.1038/s41587-022-01386-z, ISSN: 1546-1696.

Bertholet AM, Natale AM, Bisignano P, Suzuki J, Fedorenko A, Hamilton J, Brustovetsky T, Kazak L, Garrity R, Chouchani ET, Brustovetsky N, Grabe M, Kirichok Y. Mitochondrial uncouplers induce proton leak by activating AAC and UCP1. Nature [print-electronic]. 2022 Jun; 606(7912): 180-7. PMID: 35614225, PMCID: PMC9646675, PII: 10.1038/s41586-022-04747-5, DOI: 10.1038/s41586-022-04747-5, ISSN: 1476-4687.

Jatiani SS, Christie S, Leshchenko VV, Jain R, Kapoor A, Bisignano P, Lee C, Kaniskan HÜ, Edwards D, Meng F, Laganà A, Youssef Y, Wiestner A, Alinari L, Jin J, Filizola M, Aggarwal AK, Parekh S. SOX11 Inhibitors Are Cytotoxic in Mantle Cell Lymphoma. Clin Cancer Res [print-electronic]. 2021 Aug 8/15/2021; 27(16): 4652-63. PMID: 34158358, PMCID: PMC8364871, PII: 1078-0432.CCR-20-5039, DOI: 10.1158/1078-0432.CCR-20-5039, ISSN: 1557-3265.

Bisignano P, Lee MA, George A, Zuckerman DM, Grabe M, Rosenberg JM. A kinetic mechanism for enhanced selectivity of membrane transport. PLoS Comput Biol. 2020 Jul; 16(7): e1007789. PMID: 32614861, PMCID: PMC7331977, PII: PCOMPBIOL-D-19-01259, DOI: 10.1371/journal.pcbi.1007789, ISSN: 1553-7358.

George A, Bisignano P, Rosenberg JM, Grabe M, Zuckerman DM. A systems-biology approach to molecular machines: Exploration of alternative transporter mechanisms. PLoS Comput Biol. 2020 Jul; 16(7): e1007884. PMID: 32614821, PMCID: PMC7331975, PII: PCOMPBIOL-D-20-00078, DOI: 10.1371/journal.pcbi.1007884, ISSN: 1553-7358.

Redenti S, Marcovich I, De Vita T, Pérez C, De Zorzi R, Demitri N, Perez DI, Bottegoni G, Bisignano P, Bissaro M, Moro S, Martinez A, Storici P, Spalluto G, Cavalli A, Federico S. A Triazolotriazine-Based Dual GSK-3ß/CK-1d Ligand as a Potential Neuroprotective Agent Presenting Two Different Mechanisms of Enzymatic Inhibition. ChemMedChem [print-electronic]. 2019 Feb 2/5/2019; 14(3): 310-4. PMID: 30548443, DOI: 10.1002/cmdc.201800778, ISSN: 1860-7187.

Bisignano P, Ghezzi C, Jo H, Polizzi NF, Althoff T, Kalyanaraman C, Friemann R, Jacobson MP, Wright EM, Grabe M. Inhibitor binding mode and allosteric regulation of Na+-glucose symporters. Nat Commun. 2018 Dec 12/7/2018; 9(1): 5245. PMID: 30532032, PMCID: PMC6286348, PII: 10.1038/s41467-018-07700-1, DOI: 10.1038/s41467-018-07700-1, ISSN: 2041-1723.

Raleigh DR, Sever N, Choksi PK, Sigg MA, Hines KM, Thompson BM, Elnatan D, Jaishankar P, Bisignano P, Garcia-Gonzalo FR, Krup AL, Eberl M, Byrne EFX, Siebold C, Wong SY, Renslo AR, Grabe M, McDonald JG, Xu L, Beachy PA, Reiter JF. Cilia-Associated Oxysterols Activate Smoothened. Mol Cell. 2018 Oct 10/18/2018; 72(2): 316-327.e5-327.e5. PMID: 30340023, PMCID: PMC6503851, PII: S1097-2765(18)30694-4, DOI: 10.1016/j.molcel.2018.08.034, ISSN: 1097-4164.

Wahlgren WY, Dunevall E, North RA, Paz A, Scalise M, Bisignano P, Bengtsson-Palme J, Goyal P, Claesson E, Caing-Carlsson R, Andersson R, Beis K, Nilsson UJ, Farewell A, Pochini L, Indiveri C, Grabe M, Dobson RCJ, Abramson J, Ramaswamy S, Friemann R. Substrate-bound outward-open structure of a Na+-coupled sialic acid symporter reveals a new Na+ site. Nat Commun. 2018 May 5/1/2018; 9(1): 1753. PMID: 29717135, PMCID: PMC5931594, PII: 10.1038/s41467-018-04045-7, DOI: 10.1038/s41467-018-04045-7, ISSN: 2041-1723.

Paz A, Claxton DP, Kumar JP, Kazmier K, Bisignano P, Sharma S, Nolte SA, Liwag TM, Nayak V, Wright EM, Grabe M, Mchaourab HS, Abramson J. Conformational transitions of the sodium-dependent sugar transporter, vSGLT. Proc Natl Acad Sci U S A [print-electronic]. 2018 Mar 3/20/2018; 115(12): E2742-E2751-E2751. PMID: 29507231, PMCID: PMC5866573, PII: 1718451115, DOI: 10.1073/pnas.1718451115, ISSN: 1091-6490.

Bergdoll LA, Lerch MT, Patrick JW, Belardo K, Altenbach C, Bisignano P, Laganowsky A, Grabe M, Hubbell WL, Abramson J. Protonation state of glutamate 73 regulates the formation of a specific dimeric association of mVDAC1. Proc Natl Acad Sci U S A [print-electronic]. 2018 Jan 1/9/2018; 115(2): E172-E179-E179. PMID: 29279396, PMCID: PMC5777057, PII: 1715464115, DOI: 10.1073/pnas.1715464115, ISSN: 1091-6490.

Adelman JL, Ghezzi C, Bisignano P, Loo DD, Choe S, Abramson J, Rosenberg JM, Wright EM, Grabe M. Stochastic steps in secondary active sugar transport. Proc Natl Acad Sci U S A [print-electronic]. 2016 Jul 7/5/2016; 113(27): E3960-6-E3966. PMID: 27325773, PMCID: PMC4941443, PII: 1525378113, DOI: 10.1073/pnas.1525378113, ISSN: 1091-6490.

Bottegoni G, Veronesi M, Bisignano P, Kacker P, Favia AD, Cavalli A. Development and Application of a Virtual Screening Protocol for the Identification of Multitarget Fragments. ChemMedChem [print-electronic]. 2016 Jun 6/20/2016; 11(12): 1259-63. PMID: 26663255, DOI: 10.1002/cmdc.201500521, ISSN: 1860-7187.

Wardman JH, Gomes I, Bobeck EN, Stockert JA, Kapoor A, Bisignano P, Gupta A, Mezei M, Kumar S, Filizola M, Devi LA. Identification of a small-molecule ligand that activates the neuropeptide receptor GPR171 and increases food intake. Sci Signal. 2016 May 5/31/2016; 9(430): ra55. PMID: 27245612, PMCID: PMC5150984, PII: 9/430/ra55, DOI: 10.1126/scisignal.aac8035, ISSN: 1937-9145.

Di Martino RM, De Simone A, Andrisano V, Bisignano P, Bisi A, Gobbi S, Rampa A, Fato R, Bergamini C, Perez DI, Martinez A, Bottegoni G, Cavalli A, Belluti F. Versatility of the Curcumin Scaffold: Discovery of Potent and Balanced Dual BACE-1 and GSK-3ß Inhibitors. J Med Chem [print-electronic]. 2016 Jan 1/28/2016; 59(2): 531-44. PMID: 26696252, DOI: 10.1021/acs.jmedchem.5b00894, ISSN: 1520-4804.

Bisignano P, Burford NT, Shang Y, Marlow B, Livingston KE, Fenton AM, Rockwell K, Budenholzer L, Traynor JR, Gerritz SW, Alt A, Filizola M. Ligand-Based Discovery of a New Scaffold for Allosteric Modulation of the µ-Opioid Receptor. J Chem Inf Model [print-electronic]. 2015 Sep 9/28/2015; 55(9): 1836-43. PMID: 26347990, PMCID: PMC4703110, DOI: 10.1021/acs.jcim.5b00388, ISSN: 1549-960X.

Prati F, De Simone A, Bisignano P, Armirotti A, Summa M, Pizzirani D, Scarpelli R, Perez DI, Andrisano V, Perez-Castillo A, Monti B, Massenzio F, Polito L, Racchi M, Favia AD, Bottegoni G, Martinez A, Bolognesi ML, Cavalli A. Multitarget drug discovery for Alzheimer's disease: triazinones as BACE-1 and GSK-3ß inhibitors. Angew Chem Int Ed Engl [print-electronic]. 2015 Jan 1/26/2015; 54(5): 1578-82. PMID: 25504761, DOI: 10.1002/anie.201410456, ISSN: 1521-3773.

Shang Y, LeRouzic V, Schneider S, Bisignano P, Pasternak GW, Filizola M. Mechanistic insights into the allosteric modulation of opioid receptors by sodium ions. Biochemistry [print-electronic]. 2014 Aug 8/12/2014; 53(31): 5140-9. PMID: 25073009, PMCID: PMC4131901, DOI: 10.1021/bi5006915, ISSN: 1520-4995.

Bisignano P, Doerr S, Harvey MJ, Favia AD, Cavalli A, De Fabritiis G. Kinetic characterization of fragment binding in AmpC ß-lactamase by high-throughput molecular simulations [letter]. J Chem Inf Model [print-electronic]. 2014 Feb 2/24/2014; 54(2): 362-6. PMID: 24444037, DOI: 10.1021/ci4006063, ISSN: 1549-960X.

Gallina AM, Bisignano P, Bergamino M, Bordo D. PLI: a web-based tool for the comparison of protein-ligand interactions observed on PDB structures. Bioinformatics [print-electronic]. 2013 Feb 2/1/2013; 29(3): 395-7. PMID: 23196990, PII: bts691, DOI: 10.1093/bioinformatics/bts691, ISSN: 1367-4811.

Bisignano P, Lambruschini C, Bicego M, Murino V, Favia AD, Cavalli A. In silico deconstruction of ATP-competitive inhibitors of glycogen synthase kinase-3ß. J Chem Inf Model [print-electronic]. 2012 Dec 12/21/2012; 52(12): 3233-44. PMID: 23198830, DOI: 10.1021/ci300355p, ISSN: 1549-960X.

Favia AD, Bottegoni G, Nobeli I, Bisignano P, Cavalli A. SERAPhiC: a benchmark for in silico fragment-based drug design. J Chem Inf Model [print-electronic]. 2011 Nov 11/28/2011; 51(11): 2882-96. PMID: 21936510, DOI: 10.1021/ci2003363, ISSN: 1549-960X.

Bisignano P, Moran O. Molecular dynamics analysis of the wild type and dF508 mutant structures of the human CFTR-nucleotide binding domain 1. Biochimie [print-electronic]. 2010 Jan; 92(1): 51-7. PMID: 19781595, PII: S0300-9084(09)00262-4, DOI: 10.1016/j.biochi.2009.09.007, ISSN: 1638-6183.