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Ion Channels and Transporters
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Contacts

Marco Lolicato, PI

marco.lolicato@unipv.it

Cristina Arrigoni, PI

cristina.arrigoni01@unipv.it

Lab members

Marco Lolicato, PI, Associate Professor


Cristina Arrigoni, PI


Elisa Tavazzani (post-doc)


Sofia Diletta Guzzeloni (PhD student)


Manuel Decandia (Master student)


Alessandro Morea (Master student)


Viana Khojasteh (Master student)

Research

The laboratory conducts research in the field of the biophysics of ion channels and membrane transporters, with particular emphasis on the molecular mechanisms involved in neurodevelopment, neoplastic diseases, and rare disorders.


The primary goal of the laboratory is the identification and characterization of:

  1. the molecular mechanisms regulating the interactome of the KCC2 channel, which is crucial for the development and function of the nervous system;
  2. novel pharmacological approaches for GLUT1 Deficiency Syndrome (GLUT1-DS), with a strong translational perspective;
  3. the molecular structure of thermosensitive ion channels, with the aim of understanding the physical principles underlying their activation.

 

An innovative research line integrates artificial intelligence and machine learning for the de novo generation of peptide binders and mini-proteins, paving the way for new therapeutic strategies beyond the small-molecule paradigm.

The laboratory systematically employs bioinformatics tools, machine learning, and AI-assisted protein engineering to address fundamental biological questions, such as the molecular origin of membrane protein responses to physical stimuli.

From an experimental standpoint, the laboratory is capable of expressing and purifying significant quantities of protein targets for structural and functional studies. In parallel, the group explores new frontiers in rational protein design, creating proteins with novel functions from peptides and modular domains.

 

Methodologies
Electrophysiology; cell biology; expression and purification of soluble and membrane proteins and protein complexes; X-ray crystallography; cryo-electron microscopy; advanced computational methods (molecular docking, molecular dynamics, protein engineering).

Bibliography (selected)

Structural Biology and Electrophysiology

Arrigoni C., Lolicato M., Shaya D., Rohaim A., Findeisen F., Colleran C.M., Dominik P., Kim S.S., Schuermann J., Kossiakoff A.A., and Minor D.L. Quaternary structure independent folding of voltage-gated ion channel pore domain subunits. Nat Struct Mol Biol., page 2021.08.15.456357 (2022).

Lolicato M., Natale A.M., Abderemane-Ali F., Crottès D., Capponi S., Duman R., Wagner A., Rosenberg J.M., Grabe M., and Minor D.L. K2P channel C-type gating involves asymmetric selectivity filter order-disorder transitions. Science advances, 6(44) (October 2020).

Pope L., Lolicato M., and Minor D.L. Polynuclear ruthenium amines inhibit k2p channels via a ”finger in the dam” mechanism. Cell chemical biology (2020). doi: 10.1016/j.chembiol.2020.01.011.

Dang S, Feng S, Tien J, Peters CJ, Bulkley D, Lolicato M, Zhao J, Zuberbühler K, Ye W, Qi L, Chen T, Craik CS, Jan YN, Minor DL Jr, Cheng Y, Jan LY. Cryo-EM structures of the TMEM16A calcium-activated chloride channel. Nature. 2017 Dec 1;552(7685):426-429. 

Lolicato M., Arrigoni C., Mori T., Sekioka Y., Bryant C., Clark K.A., and Minor D.L. K2P2.1 (TREK-1)-activator complexes reveal a cryptic selectivity filter binding site . Nature, 547(7663):364–368 (July 2017).

Lolicato M, Riegelhaupt PM, Arrigoni C, Clark KA, Minor DL Jr. Transmembrane helix straightening and buckling underlies activation of mechanosensitive and thermosensitive K(2P) channels. Neuron. 2014 Dec 17;84(6):1198-212. doi: 10.1016/j.neuron.2014.11.017.

Arrigoni C., Rohaim A., Shaya D., Findeisen F., Stein R.A., Nurva S.R., Mishra S., Mchaourab H.S., and Minor D.L. Unfolding of a Temperature-Sensitive Domain Controls Voltage-Gated Channel Activation. Cell, 164(5):922–936 (February 2016). http://www.cell.com/cell/fulltext/S0092-8674(16)30067-8.

Shaya D, Findeisen F, Abderemane-Ali F, Arrigoni C, Wong S, Nurva SR, Loussouarn G, Minor DL Jr. Structure of a prokaryotic sodium channel pore reveals essential gating elements and an outer ion binding site common to eukaryotic channels. J Mol Biol. 2014 Jan 23;426(2):467-83.

Lolicato M, Bucchi A, Arrigoni C, Zucca S, Nardini M, Schroeder I, Simmons K, Aquila M, DiFrancesco D, Bolognesi M, Schwede F, Kashin D, Fishwick CW, Johnson AP, Thiel G, Moroni A. Cyclic dinucleotides bind the C-linker of HCN4 to control channel cAMP responsiveness. Nat Chem Biol. 2014 Jun;10(6):457-62.

Lolicato M, Nardini M, Gazzarrini S, Möller S, Bertinetti D, Herberg FW, Bolognesi M, Martin H, Fasolini M, Bertrand JA, Arrigoni C, Thiel G, Moroni A. Tetramerization dynamics of C-terminal domain underlies isoform-specific cAMP gating in hyperpolarization-activated cyclic nucleotide-gated channels. J Biol Chem. 2011 Dec 30;286(52):44811-20.

 

Protein Design and Engineering

Torielli L, Castelli M, Milani F, Heritz JA, Cayaban SJ, Hernandez J, Serapian SA, Magni A, Frasnetti E, Doria F, Pirota V, Wengert LA, Woodford MR, Lodigiani G, Bergamaschi G, Veronesi M, Bandiera T, Girotto S, Paladino A, Prodromou C, Backe SJ, Bourboulia D, Canciani A, Arrigoni C, Lolicato M, Gestwicki JE, Mollapour M, Colombo G. Design of multi-target peptide modulators for protein chaperone networks. Structure. 2025 Nov 6;33(11):1944-1957.e6.

Atomwise AIMS Program. AI is a viable alternative to high throughput screening: a 318-target study. Sci Rep. 2024 Apr 2;14(1):7526. doi: 10.1038/s41598-024-54655-z. Erratum in: Sci Rep. 2024 Sep 16;14(1):21579.

Yen TJ, Lolicato M, Thomas-Tran R, Du Bois J, Minor DL Jr. Structure of the saxiphilin:saxitoxin (STX) complex reveals a convergent molecular recognition strategy for paralytic toxins. Sci Adv. 2019 Jun 19;5(6):eaax2650.

Zhang SQ, Huang H, Yang J, Kratochvil HT, Lolicato M, Liu Y, Shu X, Liu L, DeGrado WF. Designed peptides that assemble into cross-α amyloid-like structures. Nat Chem Biol. 2018 Sep;14(9):870-875. doi: 10.1038/s41589-018-0105-5.

Ely LK, Lolicato M, David T, Lowe K, Kim YC, Samuel D, Bessette P, Garcia JL, Mikita T, Minor DL Jr, Coughlin SR. Structural Basis for Activity and Specificity of an Anticoagulant Anti-FXIa Monoclonal Antibody and a Reversal Agent. Structure. 2018 Feb 6;26(2):187-198.e4.

DiFrancesco ML, Gazzarrini S, Arrigoni C, Romani G, Thiel G, Moroni A. Engineering a Ca⁺⁺⁺-sensitive (bio)sensor from the pore-module of a potassium channel. Sensors (Basel). 2015 Feb 27;15(3):4913-24.

Arrigoni C, Schroeder I, Romani G, Van Etten JL, Thiel G, Moroni A. The voltage-sensing domain of a phosphatase gates the pore of a potassium channel. J Gen Physiol. 2013 Mar;141(3):389-95.

Lee H, Lolicato M, Arrigoni C, Minor DL Jr. Production of K2P2.1 (TREK-1) for structural studies. Methods Enzymol. 2021;653:151-188

 

Cancer Molecular Biology

Conti Nibali S, De Siervi S, Luchinat E, Magrì A, Messina A, Brocca L, Mantovani S, Oliviero B, Ahmed MH, Mondelli MU, De Pinto V, Turato C, Arrigoni C, Lolicato M. VDAC1-interacting molecules promote cell death in cancer organoids through mitochondrial-dependent metabolic interference. iScience. 2024 Apr 30;27(6):109853.

Iannucci LF, D'Erchia AM, Picardi E, Bettio D, Conca F, Surdo NC, Di Benedetto G, Musso D, Arrigoni C, Lolicato M, Vismara M, Grisan F, Salviati L, Milanesi L, Pesole G, Lefkimmiatis K. Cyclic AMP induces reversible EPAC1 condensates that regulate histone transcription. Nat Commun. 2023 Sep 8;14(1):5521.

Barbato A, Giallongo C, Giallongo S, Romano A, Scandura G, Concetta S, Zuppelli T, Lolicato M, Lazzarino G, Parrinello N, Del Fabro V, Fontana P, Aguennoz M, Li Volti G, Palumbo GA, Di Raimondo F, Tibullo D. Lactate trafficking inhibition restores sensitivity to proteasome inhibitors and orchestrates immuno-microenvironment in multiple myeloma. Cell Prolif. 2023 Apr;56(4):e13388.

Longhitano L, Vicario N, Forte S, Giallongo C, Broggi G, Caltabiano R, Barbagallo GMV, Altieri R, Raciti G, Di Rosa M, Caruso M, Parenti R, Liso A, Busi F, Lolicato M, Mione MC, Li Volti G, Tibullo D. Lactate modulates microglia polarization via IGFBP6 expression and remodels tumor microenvironment in glioblastoma. Cancer Immunol Immunother. 2023 Jan;72(1):1-20. doi: 10.1007/s00262-022-03215-3. Epub 2022 Jun 3. Erratum in: Cancer Immunol Immunother. 2023 Jan;72(1):21.