8ehw | pdb_00008ehw

cryo-EM structure of TMEM63A in nanodisc

Structural highlights

8ehw is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 3.8Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

CSCL1_HUMAN The disease is caused by variants affecting the gene represented in this entry.

Function

CSCL1_HUMAN Acts as an osmosensitive calcium-permeable cation channel (PubMed:30382938, PubMed:31587869). Mechanosensitive ion channel that converts mechanical stimuli into a flow of ion (PubMed:30382938, PubMed:31587869, PubMed:37543036).[UniProtKB:Q91YT8]^[1] ^[2] ^[3]

Publication Abstract from PubMed

OSCA/TMEM63s form mechanically activated (MA) ion channels in plants and animals, respectively. OSCAs and related TMEM16s and transmembrane channel-like (TMC) proteins form homodimers with two pores. Here, we uncover an unanticipated monomeric configuration of TMEM63 proteins. Structures of TMEM63A and TMEM63B (referred to as TMEM63s) revealed a single highly restricted pore. Functional analyses demonstrated that TMEM63s are bona fide mechanosensitive ion channels, characterized by small conductance and high thresholds. TMEM63s possess evolutionary variations in the intracellular linker IL2, which mediates dimerization in OSCAs. Replacement of OSCA1.2 IL2 with TMEM63A IL2 or mutations to key variable residues resulted in monomeric OSCA1.2 and MA currents with significantly higher thresholds. Structural analyses revealed substantial conformational differences in the mechano-sensing domain IL2 and gating helix TM6 between TMEM63s and OSCA1.2. Our studies reveal that mechanosensitivity in OSCA/TMEM63 channels is affected by oligomerization and suggest gating mechanisms that may be shared by OSCA/TMEM63, TMEM16, and TMC channels.

TMEM63 proteins function as monomeric high-threshold mechanosensitive ion channels.,Zheng W, Rawson S, Shen Z, Tamilselvan E, Smith HE, Halford J, Shen C, Murthy SE, Ulbrich MH, Sotomayor M, Fu TM, Holt JR Neuron. 2023 Oct 18;111(20):3195-3210.e7. doi: 10.1016/j.neuron.2023.07.006. Epub , 2023 Aug 4. PMID:37543036^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Murthy SE, Dubin AE, Whitwam T, Jojoa-Cruz S, Cahalan SM, Mousavi SAR, Ward AB, Patapoutian A. OSCA/TMEM63 are an Evolutionarily Conserved Family of Mechanically Activated Ion Channels. Elife. 2018 Nov 1;7:e41844. PMID:30382938 doi:10.7554/eLife.41844
↑ Yan H, Helman G, Murthy SE, Ji H, Crawford J, Kubisiak T, Bent SJ, Xiao J, Taft RJ, Coombs A, Wu Y, Pop A, Li D, de Vries LS, Jiang Y, Salomons GS, van der Knaap MS, Patapoutian A, Simons C, Burmeister M, Wang J, Wolf NI. Heterozygous Variants in the Mechanosensitive Ion Channel TMEM63A Result in Transient Hypomyelination during Infancy. Am J Hum Genet. 2019 Nov 7;105(5):996-1004. PMID:31587869 doi:10.1016/j.ajhg.2019.09.011
↑ Zheng W, Rawson S, Shen Z, Tamilselvan E, Smith HE, Halford J, Shen C, Murthy SE, Ulbrich MH, Sotomayor M, Fu TM, Holt JR. TMEM63 proteins function as monomeric high-threshold mechanosensitive ion channels. Neuron. 2023 Jul 28:S0896-6273(23)00512-3. PMID:37543036 doi:10.1016/j.neuron.2023.07.006
↑ Zheng W, Rawson S, Shen Z, Tamilselvan E, Smith HE, Halford J, Shen C, Murthy SE, Ulbrich MH, Sotomayor M, Fu TM, Holt JR. TMEM63 proteins function as monomeric high-threshold mechanosensitive ion channels. Neuron. 2023 Jul 28:S0896-6273(23)00512-3. PMID:37543036 doi:10.1016/j.neuron.2023.07.006

Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] Murthy SE, Dubin AE, Whitwam T, Jojoa-Cruz S, Cahalan SM, Mousavi SAR, Ward AB, Patapoutian A. OSCA/TMEM63 are an Evolutionarily Conserved Family of Mechanically Activated Ion Channels. Elife. 2018 Nov 1;7:e41844. PMID:30382938 doi:10.7554/eLife.41844

[2] Yan H, Helman G, Murthy SE, Ji H, Crawford J, Kubisiak T, Bent SJ, Xiao J, Taft RJ, Coombs A, Wu Y, Pop A, Li D, de Vries LS, Jiang Y, Salomons GS, van der Knaap MS, Patapoutian A, Simons C, Burmeister M, Wang J, Wolf NI. Heterozygous Variants in the Mechanosensitive Ion Channel TMEM63A Result in Transient Hypomyelination during Infancy. Am J Hum Genet. 2019 Nov 7;105(5):996-1004. PMID:31587869 doi:10.1016/j.ajhg.2019.09.011

[3] Zheng W, Rawson S, Shen Z, Tamilselvan E, Smith HE, Halford J, Shen C, Murthy SE, Ulbrich MH, Sotomayor M, Fu TM, Holt JR. TMEM63 proteins function as monomeric high-threshold mechanosensitive ion channels. Neuron. 2023 Jul 28:S0896-6273(23)00512-3. PMID:37543036 doi:10.1016/j.neuron.2023.07.006

[4] Zheng W, Rawson S, Shen Z, Tamilselvan E, Smith HE, Halford J, Shen C, Murthy SE, Ulbrich MH, Sotomayor M, Fu TM, Holt JR. TMEM63 proteins function as monomeric high-threshold mechanosensitive ion channels. Neuron. 2023 Jul 28:S0896-6273(23)00512-3. PMID:37543036 doi:10.1016/j.neuron.2023.07.006

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8ehw | pdb_00008ehw

cryo-EM structure of TMEM63A in nanodisc

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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