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1.A.82. The LHFPL Tetraspan Protein (LTSP) Family

Mammalian hair cells are mechanosensors for the perception of sound, acceleration, and fluid motion. Mechanotransduction channels in hair cells are gated by tip links, which connect the stereocilia of a hair cell in the direction of their mechanical sensitivity. The molecular constituents of the mechanotransduction channels of hair cells are numerous. Xiong et al. (2012) showed that mechanotransduction is impaired in mice lacking the tetraspan membrane protein of hair cell stereocilia, TMHS, also known as lipoma HMGIC fusion partner-like 5, LHFPL5). However, TMC1 is likely to be a pore-forming subunit of the transduction channel of cochlear hair cells that is mechanically gated by tension on tip links in the stereocilia bundle (Mahendrasingam and Furness 2019).

TMHS binds to the tip-link component PCDH15 and regulates tip-link assembly, a process that is disrupted by deafness-causing Tmhs mutations. TMHS also regulates transducer channel conductance and is required for fast channel adaptation. TMHS therefore resembles other ion channel regulatory subunits such as the transmembrane alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor regulatory proteins (TARPs) of AMPA receptors that facilitate channel transport and regulate the properties of pore-forming channel subunits. TMHS is an integral component of the hair cell's mechanotransduction machinery that functionally couples PCDH15 to the transduction channel (Xiong et al. 2012). Tmc1 and Tmc2 (TC#s 1.A.17.4.6 and 1.A.17.4.1, respectively) play important roles and are required for normal function of cochlear hair cells, possibly as Ca2+ channels or Ca2+ channel subunits (Kim and Fettiplace 2013).  Direct interactions between TMHS, PCDH15 and Tmc1 and Tmc2 have been demonstrated (Maeda et al. 2014; Beurg et al. 2015).

Mechanotransduction channels in hair cells are gated by tip links.  Zhao et al. 2014 showed that the transmembrane inner ear protein, TMIE (TC# 9.A.30), forms a ternary complex with the tip-link component PCDH15 and its binding partner TMHS/LHFPL5 (TC# 1.A.82). Alternative splicing of the PCDH15 cytoplasmic domain regulates formation of this ternary complex. Transducer currents are abolished by a homozygous Tmie-null mutation, and subtle Tmie mutations that disrupt interactions between TMIE and tip links affect transduction, suggesting that TMIE is an essential component of the hair cell's mechanotransduction machinery that functionally couples the tip link to the transduction channel. The multisubunit composition of the transduction complex and the regulation of complex assembly by alternative splicing is likely critical for regulating channel properties in different hair cells and along the cochlea's tonotopic axis (Zhao et al. 2014).

Auditory hair cells are restricted to vertebrates (Lumpkin et al. 2010), and the members listed under TC # 1.A.82 include proteins from non-vertebrates including the salmon louse (D3PJ72), the water flea (E9FU04) and the european centipede (T1INH4 ). Furthermore, there is uncertainty about the subunit composition of the vertebrate hair cell mechanotransduction channel (see Wu and Müller 2016 and Fettiplace 2016). For this reason, we have changed the name of this family from the 'Hair Cell Mechanotransduction Channel' (HCMC) (Chou et al. 2017) to the “LHFPL Tetraspan Protein”  (LTSP) Family.  This name is based on shared domain/structures rather than and uncertain biochemical function (Paul Denny, personal communication).

References associated with 1.A.82 family:

Beurg, M., A.C. Goldring, and R. Fettiplace. (2015). The effects of Tmc1 Beethoven mutation on mechanotransducer channel function in cochlear hair cells. J Gen Physiol 146: 233-243. 26324676
Beurg, M., W. Xiong, B. Zhao, U. Müller, and R. Fettiplace. (2015). Subunit determination of the conductance of hair-cell mechanotransducer channels. Proc. Natl. Acad. Sci. USA 112: 1589-1594. 25550511
Chou, A., A. Lee, K.J. Hendargo, V.S. Reddy, M.A. Shlykov, H. Kuppusamykrishnan, A. Medrano-Soto, and M.H. Saier, Jr. (2017). Characterization of the Tetraspan Junctional Complex (4JC) superfamily. Biochim. Biophys. Acta. 1859: 402-414. 27916633
Davenport, E.C., V. Pendolino, G. Kontou, T.P. McGee, D.F. Sheehan, G. López-Doménech, M. Farrant, and J.T. Kittler. (2017). An Essential Role for the Tetraspanin LHFPL4 in the Cell-Type-Specific Targeting and Clustering of Synaptic GABA Receptors. Cell Rep 21: 70-83. 28978485
Fettiplace, R. (2016). Is TMC1 the Hair Cell Mechanotransducer Channel? Biophys. J. 111: 3-9. 27410728
Ge, J., J. Elferich, A. Goehring, H. Zhao, P. Schuck, and E. Gouaux. (2018). Structure of mouse protocadherin 15 of the stereocilia tip link in complex with LHFPL5. Elife 7:. 30070639
Han, W., R.D. Shepard, and W. Lu. (2020). Regulation of GABARs by Transmembrane Accessory Proteins. Trends Neurosci. [Epub: Ahead of Print] 33234346
Lumpkin, E.A., K.L. Marshall, and A.M. Nelson. (2010). The cell biology of touch. J. Cell Biol. 191: 237-248. 20956378
Maeda, R., K.S. Kindt, W. Mo, C.P. Morgan, T. Erickson, H. Zhao, R. Clemens-Grisham, P.G. Barr-Gillespie, and T. Nicolson. (2014). Tip-link protein protocadherin 15 interacts with transmembrane channel-like proteins TMC1 and TMC2. Proc. Natl. Acad. Sci. USA 111: 12907-12912. 25114259
Mahendrasingam, S. and D.N. Furness. (2019). Ultrastructural localization of the likely mechanoelectrical transduction channel protein, transmembrane-like channel 1 (TMC1) during development of cochlear hair cells. Sci Rep 9: 1274. 30718571
Ogun, O. and M. Zallocchi. (2014). Clarin-1 acts as a modulator of mechanotransduction activity and presynaptic ribbon assembly. J. Cell Biol. 207: 375-391. 25365995
Petit, M.M., E.F. Schoenmakers, C. Huysmans, J.M. Geurts, N. Mandahl, and W.J. Van de Ven. (1999). LHFP, a novel translocation partner gene of HMGIC in a lipoma, is a member of a new family of LHFP-like genes. Genomics 57: 438-441. 10329012
Wu, Z. and U. Müller. (2016). Molecular Identity of the Mechanotransduction Channel in Hair Cells: Not Quiet There Yet. J. Neurosci. 36: 10927-10934. 27798175
Wu, Z., N. Grillet, B. Zhao, C. Cunningham, S. Harkins-Perry, B. Coste, S. Ranade, N. Zebarjadi, M. Beurg, R. Fettiplace, A. Patapoutian, and U. Müller. (2016). Mechanosensory hair cells express two molecularly distinct mechanotransduction channels. Nat Neurosci. [Epub: Ahead of Print] 27893727
Xiong, W., N. Grillet, H.M. Elledge, T.F. Wagner, B. Zhao, K.R. Johnson, P. Kazmierczak, and U. Müller. (2012). TMHS Is an Integral Component of the Mechanotransduction Machinery of Cochlear Hair Cells. Cell 151: 1283-1295. 23217710
Yu, X., Q. Zhao, X. Li, Y. Chen, Y. Tian, S. Liu, W. Xiong, and P. Huang. (2020). Deafness mutation D572N of TMC1 destabilizes TMC1 expression by disrupting LHFPL5 binding. Proc. Natl. Acad. Sci. USA 117: 29894-29903. 33168709
Zhao, B., Z. Wu, N. Grillet, L. Yan, W. Xiong, S. Harkins-Perry, and U. Müller. (2014). TMIE is an essential component of the mechanotransduction machinery of cochlear hair cells. Neuron. 84: 954-967. 25467981