Journal club
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JOURNAL CLUB
Journal club Mark T. Young 1 Received: 28 July 2020 / Accepted: 3 August 2020 # Springer Nature B.V. 2020
Commentary Pannexins are a family of three non-selective anion channels in humans (PanX1, PanX2 and PanX3), proposed to play roles in nucleotide release (particularly during apoptosis), the regulation of blood pressure, neuropathic pain, cancer progression and oocyte development (see references in Michalski et al. [1], Deng et al. [2] and Ruan et al. [3]). Pannexins can be activated by multiple stimuli including changes in membrane potential, shear stress, elevated extracellular potassium, and interactions with other proteins (e.g. caspases) (Dahl G (2018) FEBS Lett. 592:3201-9). The physiological importance of pannexins makes them key drug targets, but the fundamental understanding of their structure-function relationship has been hampered by a lack of high-resolution structural information, compounded by a lack of substantial amino acid sequence homology to other proteins thought to be in a similar structural family (e.g. connexins). Single particle cryoEM has revolutionised structural biology, in particular the study of membrane protein structure, often permitting the study of wild-type proteins in a lipid-containing environment and not requiring either the production of tens of milligrammes of protein or the formation of 3D crystals (Cheng Y (2018) Science 361:876–80). Michalski et al. [1], Deng et al. [2] and Ruan et al. [3] have each used this technique to determine the 3D structure of the 428 amino acid PanX1 channel, either from Xenopus tropicalis (Michalski et al. [1], Deng et al. [2]) or human (Deng et al. [2] and Ruan et al. [3]). It is an indication of the competitive nature of the research field that three additional papers reporting cryoEM structures of human PanX1 were recently presented back to back in the May edition of Cell Research (Qu et al. (2020) Cell Res. 30: 446–448, Jin et al. (2020) Cell Res. 30: * Mark T. Young [email protected] 1
School of Biosciences, Cardiff University, Sir Martin Evans Building, Museum Avenue, Cardiff CF10 3AX, Wales
449–451 and Mou et al. (2020) Cell Res. 30: 452–454), and so a wealth of structural information has been provided in a relatively short time. The methodology used in each of the six papers was subtly different; constructs, expression systems, purification procedures and data collection/analysis methods vary, and the final resolution of each structure is different, but all report the same key findings. Each PanX1 monomer is composed of a bundle of 4 TM helices, with TM1 lining the pore, two extracellular loops (ECL1 and 2; composed of a mixture of α-helix and βstrands) and largely helical intracellular loop (ICL) and Cterminal domains. The overall protomer has structural homology with other large pore forming channels such as connexins and innexins. The biological unit is an inverted cone-shaped heptamer narrower in the extracellular domain than the intracellular domain. This is contrary to previous low-resolution studies which sug
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