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Crystal structure of coiled-coil region of mouse TMEM266
Structural highlights
FunctionTM266_MOUSE Voltage-sensor protein present on the post-synaptic side of glutamatergic mossy fibers and granule cells in the cerebellum. Despite the presence of a voltage-sensor segment, does not form a functional ion channel and its precise role remains unclear. Undergoes both rapid and slow structural rearrangements in response to changes in voltage. Contains a zinc-binding site that can regulate the slow conformational transition.[UniProtKB:Q2M3C6] Publication Abstract from PubMedVoltage-sensing proteins generally consist of voltage-sensor domains and pore-gate domains, forming the voltage-gated ion channels. However, there are several unconventional voltage-sensor proteins that lack pore-gate domains, conferring them unique voltage-sensing machinery. TMEM266, which is expressed in cerebellum granule cells, is one of the interesting voltage-sensing proteins that has a putative intracellular coiled-coil and a functionally unidentified cytosolic region instead of a pore-gate domain. Here, we approached the molecular function of TMEM266 by performing co-immunoprecipitation experiments. We unexpectedly discovered that TMEM266 proteins natively interact with the novel short form splice variants that only have voltage-sensor domains and putative cytosolic coiled-coil region in cerebellum. The crystal structure of coiled-coil region of TMEM266 suggested that these coiled-coil regions play significant roles in forming homodimers. In vitro expression experiments supported the idea that short form TMEM266 (sTMEM266) or full length TMEM266 (fTMEM266) form homodimers. We also performed proximity labeling mass spectrometry analysis for fTMEM266 and sTMEM266 using Neuro-2A, neuroblastoma cells, and fTMEM266 showed more interacting molecules than sTMEM266, suggesting that the C-terminal cytosolic region in fTMEM266 binds to various targets. Finally, TMEM266-deficient animals showed the moderate abnormality in open-field test. The present study provides clues about the novel voltage-sensing mechanism mediated by TMEM266. Insight into the function of a unique voltage-sensor protein (TMEM266) and its short form in mouse cerebellum.,Kawai T, Narita H, Konno K, Akter S, Andriani RT, Iwasaki H, Nishikawa S, Yokoi N, Fukata Y, Fukata M, Wiriyasermkul P, Kongpracha P, Nagamori S, Takao K, Miyakawa T, Abe M, Sakimura K, Watanabe M, Nakagawa A, Okamura Y Biochem J. 2022 Jun 17;479(11):1127-1145. doi: 10.1042/BCJ20220033. PMID:35574701[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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