From cardiac arrhythmia to epilepsy – Ion channels in health and disease
Keywords: Cryo-EM, X-ray crystallography, electrophysiology
Our lab studies the structure and function of ion channels, membrane proteins that mediate electrical signaling in excitable cells. They are essential for neuronal signaling, the beating of our hearts, the contraction of muscle, and much more. Ion channel genes are targeted by thousands of genetic variants that result in ‘channelopathies’, a set of severe disorders ranging from inherited cardiac arrhythmias to chronic pain and congenital epilepsy. As humans age, the regulation of ion channels frequently goes haywire, leading to a range of acquired disorders.
How do ion channels gate? How do ion channels ‘remember’ past events? How do auxiliary proteins, small molecules, and post-translational modifications change their behavior? How do they assemble into larger complexes? How do disease-associated mutations change their function? We try to answer these questions via various methods.
As ion channels are complex and dynamic proteins, we utilize a combination of methods to study their behavior. This includes X-ray crystallography and cryo-electron microscopy to study their 3D structures, and electrophysiology to measure the electrical currents generated when the channels open. Current projects are focused on the communication between L-type calcium channels and Ryanodine Receptors, and on calcium-dependent ‘memory’ mechanisms in sodium and calcium channels. For more information see: http://crg.ubc.ca/VanPetegem/
Woll K, Haji-Ghassemi O, Van Petegem F (2021) Pathological conformations of disease mutant Ryanodine Receptors revealed by cryo-EM. Nature Comm. 12:807
Ma R, Haji-Ghassemi O, Ma D, Jiang H, Lin L, Yao L, Samurkas A, Li Y, Wang Y, Cao P, Wu S, Zhang Y, Murayama T, Moussian B, Van Petegem F * , Yuchi Z* . (2020) Structural basis for diamide modulation of ryanodine receptor. Nature Chem Biol. 16:12461254 *co-corresponding authors.
Gardill B, Tung C-C, Van Petegem F (2019) Crystal structures of Ca2+-calmodulin bound to NaV Cterminal regions suggest role for EF-hand domain in binding and inactivation. Proc. Natl. Acad. Sci. USA. 116,10763-10772.
Haji-Ghassemi O, Yuchi Z, Van Petegem F (2019) The Cardiac Ryanodine Receptor Phosphorylation Hot Spot Embraces PKA in a Phosphorylation-Dependent Manner. Molecular Cell. 75, 1-14.
Wang K, Holt C, Lu J, Brohus M, Larsen KT, Overgaard MT, Wimmer R, Van Petegem F (2018) Arrhythmia mutations in Calmodulin cause conformational changes that affect interactions with the cardiac voltage-gated calcium channel. Proc. Natl. Acad. Sci. USA. 115:E10556-E10565.
Wong King Yuen SM, Campiglio M, Tung CC, Flucher BE, Van Petegem F (2017) Structural insights into binding of STAC proteins to voltage-gated calcium channels. Proc. Natl. Acad. Sci. USA.114:E9520- E9528.
Das S, Gilchrist J, Bosmans F*, Van Petegem F* (2016) Binary architecture of the NaV1.2-beta2 signaling complex. Elife 5:e10960. *co-corresponding authors.
Yuchi Z, Wong King Yuen S, Lau K, Underhill AQ, Cornea R, Fessenden J, Van Petegem F (2015) Crystal structures of Ryanodine Receptor SPRY1 and tandem-repeat domains reveal a critical FKBP12 binding determinant. Nature Comm. 6,7947.
Lau K, Van Petegem F (2014) Crystal structures of wild-type and disease mutant forms of the ryanodine receptor SPRY2 domain. Nature Comm. 5:5397
Kimlicka L, Lau K, Tung CC, Van Petegem F (2013) Disease mutations in the Ryanodine Receptor Nterminal region couple to a mobile intersubunit interface. Nature Comm. 4:1506.
Gilchrist J, Das S, Van Petegem F*, Bosmans F* (2013) Crystallographic insights into sodium channel modulation by the beta4 subunit. Proc. Natl. Acad. Sci. USA. 110:E5016-5024 *co-corresponding authors.
Sarhan MF, Tung CC, Van Petegem F*, Ahern CA* (2012) Crystallographic basis for calcium regulation of sodium channels. Proc. Natl. Acad. Sci. USA 109:3558-3563. *co-corresponding authors.
Tung C-C, Lobo PA, Kimlicka L, Van Petegem F (2010) The ryanodine receptor N-terminal disease hot spot forms a cytoplasmic vestibule. Nature 468, 585-588.
Van Petegem F, Clark KA, Chatelain FC, Minor DL Jr. (2004) Structure of a complex between a voltage-gated calcium channel beta-subunit and an alpha-subunit domain. Nature 429,671-675.