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?
- Falzone, ME, Feng, Z, Alvarenga, OE, Pan, Y, Lee, B, Cheng, X et al.. TMEM16 scramblases thin the membrane to enable lipid scrambling. Nat Commun. 2022;13 (1):2604. doi: 10.1038/s41467-022-30300-z. PubMed PMID:35562175 PubMed Central PMC9095706.
- Fortea, E, Accardi, A. A quantitative flux assay for the study of reconstituted Cl- channels and transporters. Methods Enzymol. 2021;652 :243-272. doi: 10.1016/bs.mie.2021.01.026. PubMed PMID:34059284 .
- Accardi, A. Not so transport incompetent after all: Revisiting a CLC-7 mutant sheds new mechanistic light on lysosomal physiology. J Gen Physiol. 2021;153 (4):. doi: 10.1085/jgp.202012805. PubMed PMID:33570555 PubMed Central PMC7883728.
- Leisle, L, Xu, Y, Fortea, E, Lee, S, Galpin, JD, Vien, M et al.. Divergent Cl- and H+ pathways underlie transport coupling and gating in CLC exchangers and channels. Elife. 2020;9 :. doi: 10.7554/eLife.51224. PubMed PMID:32343228 PubMed Central PMC7274781.
- Falzone, ME, Accardi, A. Reconstitution of Proteoliposomes for Phospholipid Scrambling and Nonselective Channel Assays. Methods Mol Biol. 2020;2127 :207-225. doi: 10.1007/978-1-0716-0373-4_15. PubMed PMID:32112325 PubMed Central PMC7297447.
- Zajac, M, Chakraborty, K, Saha, S, Mahadevan, V, Infield, DT, Accardi, A et al.. What biologists want from their chloride reporters - a conversation between chemists and biologists. J Cell Sci. 2020;133 (2):. doi: 10.1242/jcs.240390. PubMed PMID:31974277 .
- Khelashvili, G, Cheng, X, Falzone, ME, Doktorova, M, Accardi, A, Weinstein, H et al.. Membrane lipids are both the substrates and a mechanistically responsive environment of TMEM16 scramblase proteins. J Comput Chem. 2020;41 (6):538-551. doi: 10.1002/jcc.26105. PubMed PMID:31750558 PubMed Central PMC7261202.
- 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 PubMed Central PMC8189574.
- Accardi, A. Structure and gating of CLC channels and exchangers. J Physiol. 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 PubMed Central PMC7263376.
- 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.