Alessio Accardi, Ph.D.
- Associate Professor of Physiology and Biophysics in Anesthesiology (primary appointment)
- Associate Professor of Biochemistry
525 East 68th Street, Room A-1040
New York, NY 10021
Work in my lab is aimed at uncovering the molecular and structural underpinnings regulating the movement of charged ions across cellular membranes. This process results in the electrical currents underlying scores of fundamental physiological processes such as the neuronal action potential, muscle contraction, insulin secretion and signal transduction. Two classes of membrane proteins mediate transmembrane ion movement through thermodynamically opposing mechanisms: the transporter use chemical energy to create ionic gradients while the ion channels dissipate the gradients by allowing ion diffusion. Mutations in both kinds of proteins lead to the creation of structures whose functional consequences underlie a variety of genetically inherited disorders.
My research focuses in two main areas:
- Understanding the structural and functional underpinnings of genetic diseases associated to ion channels and transporters.
- Uncovering the biophysical mechanism regulating the function of these proteins.
To investigate these areas my laboratory uses a combination of techniques, ranging from X-ray crystallography, to single channel and macroscopic current electrophysiology, calorimetry, reconstitution into synthetic lipid bilayers and other biochemical assays.Our work focuses on the CLC (Chloride Channels) protein family whose members are central to the proper function of several physiological processes, a role highlighted by the five human diseases associated to the production of defective CLC proteins. One of these diseases is Bartter’s syndrome, which comprises a collection of recessive renal disorders characterized by salt wasting, low blood pressure and hypercalciuria with a risk of renal stones –all consequences of reduced salt reuptake by the thick ascending limb of Henle. In renal cells, the basolateral Cl- channel complex is formed by an association between the CLC-Kb channel and Barttin (a regulatory β-subunit), and mutations in either lead to Bartter’s syndrome. We are currently investigating how these two proteins associate, and how this is disrupted in the disease.
Not only the CLCs play key roles in human physiology, but they have been a veritable treasure trove of unexpected biophysical and structural properties. To our surprise we have recently discovered that not all the CLCs are chloride selective ion channels, as it had been believed for about 30 years, but rather the family is deeply divided in half: some members are bona-fide ion channels, while others are active transporters! With the CLCs sitting at the evolutionary cusp bridging active and passive transport proteins we can probe the ever-thinning barrier between these two protein classes to unprecedented detail. Both CLCs sub-classes share a single structural organization, punctuated by highly conserved sequences and, yet, have opposite thermodynamic functions. How is that possible? Can we identify the essential differences that could allow transfer of function from one group to the other?
- Khelashvili, G, Falzone, ME, Cheng, X, Lee, BC, Accardi, A, Weinstein, H et al.. Dynamic modulation of the lipid translocation groove generates a conductive ion channel in Ca2+-bound nhTMEM16. Nat Commun. 2019;10 (1):4972. doi: 10.1038/s41467-019-12865-4. PubMed PMID:31672969 PubMed Central PMC6823365.
- Bushell, SR, Pike, ACW, Falzone, ME, Rorsman, NJG, Ta, CM, Corey, RA et al.. The structural basis of lipid scrambling and inactivation in the endoplasmic reticulum scramblase TMEM16K. Nat Commun. 2019;10 (1):3956. doi: 10.1038/s41467-019-11753-1. PubMed PMID:31477691 PubMed Central PMC6718402.
- Falzone, ME, Rheinberger, J, Lee, BC, Peyear, T, Sasset, L, Raczkowski, AM et al.. Structural basis of Ca2+-dependent activation and lipid transport by a TMEM16 scramblase. Elife. 2019;8 :. doi: 10.7554/eLife.43229. PubMed PMID:30648972 PubMed Central PMC6355197.
- Lee, BC, Khelashvili, G, Falzone, M, Menon, AK, Weinstein, H, Accardi, A et al.. Gating mechanism of the extracellular entry to the lipid pathway in a TMEM16 scramblase. Nat Commun. 2018;9 (1):3251. doi: 10.1038/s41467-018-05724-1. PubMed PMID:30108217 PubMed Central PMC6092359.
- Malvezzi, M, Andra, KK, Pandey, K, Lee, BC, Falzone, ME, Brown, A et al.. Out-of-the-groove transport of lipids by TMEM16 and GPCR scramblases. Proc. Natl. Acad. Sci. U.S.A. 2018;115 (30):E7033-E7042. doi: 10.1073/pnas.1806721115. PubMed PMID:29925604 PubMed Central PMC6065010.
- Falzone, ME, Malvezzi, M, Lee, BC, Accardi, A. Known structures and unknown mechanisms of TMEM16 scramblases and channels. J. Gen. Physiol. 2018;150 (7):933-947. doi: 10.1085/jgp.201711957. PubMed PMID:29915161 PubMed Central PMC6028493.
- Vien, M, Basilio, D, Leisle, L, Accardi, A. Probing the conformation of a conserved glutamic acid within the Cl- pathway of a CLC H+/Cl- exchanger. J. Gen. Physiol. 2017;149 (4):523-529. doi: 10.1085/jgp.201611682. PubMed PMID:28246117 PubMed Central PMC5379918.
- Lee, BC, Menon, AK, Accardi, A. The nhTMEM16 Scramblase Is Also a Nonselective Ion Channel. Biophys. J. 2016;111 (9):1919-1924. doi: 10.1016/j.bpj.2016.09.032. PubMed PMID:27806273 PubMed Central PMC5103024.
- Accardi, A. CELL SIGNALING. Lipids link ion channels and cancer. Science. 2015;349 (6250):789-90. doi: 10.1126/science.aad0874. PubMed PMID:26293939 .
- Accardi, A. Structure and gating of CLC channels and exchangers. J. Physiol. (Lond.). 2015;593 (18):4129-38. doi: 10.1113/JP270575. PubMed PMID:26148215 PubMed Central PMC4594288.
- Basilio, D, Accardi, A. A Proteoliposome-Based Efflux Assay to Determine Single-molecule Properties of Cl- Channels and Transporters. J Vis Exp. 2015; (98):. doi: 10.3791/52369. PubMed PMID:25938223 PubMed Central PMC4541587.
- Accardi, A. Unveiling the secret lives of glutamate transporters: VGLUTs engage in multiple transport modes. Neuron. 2014;84 (6):1110-2. doi: 10.1016/j.neuron.2014.12.008. PubMed PMID:25521371 .
- Picollo, A, Malvezzi, M, Accardi, A. TMEM16 proteins: unknown structure and confusing functions. J. Mol. Biol. 2015;427 (1):94-105. doi: 10.1016/j.jmb.2014.09.028. PubMed PMID:25451786 PubMed Central PMC4277903.
- Corral-Rodríguez, MÁ, Stuiver, M, Abascal-Palacios, G, Diercks, T, Oyenarte, I, Ereño-Orbea, J et al.. Nucleotide binding triggers a conformational change of the CBS module of the magnesium transporter CNNM2 from a twisted towards a flat structure. Biochem. J. 2014;464 (1):23-34. doi: 10.1042/BJ20140409. PubMed PMID:25184538 .
- Basilio, D, Noack, K, Picollo, A, Accardi, A. Conformational changes required for H(+)/Cl(-) exchange mediated by a CLC transporter. Nat. Struct. Mol. Biol. 2014;21 (5):456-63. doi: 10.1038/nsmb.2814. PubMed PMID:24747941 PubMed Central PMC4040230.
- Terashima, H, Picollo, A, Accardi, A. Purified TMEM16A is sufficient to form Ca2+-activated Cl- channels. Proc. Natl. Acad. Sci. U.S.A. 2013;110 (48):19354-9. doi: 10.1073/pnas.1312014110. PubMed PMID:24167264 PubMed Central PMC3845129.
- Malvezzi, M, Chalat, M, Janjusevic, R, Picollo, A, Terashima, H, Menon, AK et al.. Ca2+-dependent phospholipid scrambling by a reconstituted TMEM16 ion channel. Nat Commun. 2013;4 :2367. doi: 10.1038/ncomms3367. PubMed PMID:23996062 PubMed Central PMC3970400.
- Picollo, A, Xu, Y, Johner, N, Bernèche, S, Accardi, A. Synergistic substrate binding determines the stoichiometry of transport of a prokaryotic H(+)/Cl(-) exchanger. Nat. Struct. Mol. Biol. 2012;19 (5):525-31, S1. doi: 10.1038/nsmb.2277. PubMed PMID:22484316 PubMed Central PMC3348462.
- Ying, SW, Tibbs, GR, Picollo, A, Abbas, SY, Sanford, RL, Accardi, A et al.. PIP2-mediated HCN3 channel gating is crucial for rhythmic burst firing in thalamic intergeniculate leaflet neurons. J. Neurosci. 2011;31 (28):10412-23. doi: 10.1523/JNEUROSCI.0021-11.2011. PubMed PMID:21753018 PubMed Central PMC6623048.
- Hara, Y, Balci-Hayta, B, Yoshida-Moriguchi, T, Kanagawa, M, Beltrán-Valero de Bernabé, D, Gündeşli, H et al.. A dystroglycan mutation associated with limb-girdle muscular dystrophy. N. Engl. J. Med. 2011;364 (10):939-46. doi: 10.1056/NEJMoa1006939. PubMed PMID:21388311 PubMed Central PMC3071687.