Structural relationship between the putative hair cell mechanotransduction channel TMC1 and TMEM16 proteins

被引：87

作者：

Ballesteros, Angela ^{[1
]}

Fenollar-Ferrer, Cristina ^{[2
,3
,4
]}

Swartz, Kenton Jon ^{[1
]}

机构：

[1] Natl Inst Neurol Disorders & Stroke, Mol Physiol & Biophys Sect, Natl Inst Hlth, Bethesda, MD 20892 USA

[2] Natl Inst Mental Hlth, Lab Mol & Cellular Neurobiol, Natl Inst Hlth, Bethesda, MD USA

[3] Natl Inst Deafness & Other Commun Disorders, Lab Mol Genet, Natl Inst Hlth, Bethesda, MD USA

[4] Natl Inst Deafness & Other Commun Disorders, Mol Biol & Genet Sect, Natl Inst Hlth, Bethesda, MD USA

来源：

ELIFE | 2018年 / 7卷

关键词：

MECHANOELECTRICAL TRANSDUCTION; MECHANICAL TRANSDUCTION; SEQUENCE ALIGNMENTS; HEARING-LOSS; CONDUCTANCE; MUTATION; PORE; DIHYDROSTREPTOMYCIN; VISUALIZATION; SIMILARITY;

D O I：

10.7554/eLife.38433

中图分类号：

Q [生物科学];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

The hair cell mechanotransduction (MET) channel complex is essential for hearing, yet it's molecular identity and structure remain elusive. The transmembrane channel-like 1 (TMC1) protein localizes to the site of the MET channel, interacts with the tip-link responsible for mechanical gating, and genetic alterations in TMC1 alter MET channel properties and cause deafness, supporting the hypothesis that TMC1 forms the MET channel. We generated a model of TMC1 based on X-ray and cryo-EM structures of TMEM16 proteins, revealing the presence of a large cavity near the protein-lipid interface that also harbors the Beethoven mutation, suggesting that it could function as a permeation pathway. We also find that hair cells are permeable to 3 kDa dextrans, and that dextran permeation requires TMC1/2 proteins and functional MET channels, supporting the presence of a large permeation pathway and the hypothesis that TMC1 is a pore forming subunit of the MET channel complex.

引用

页数：26

共 103 条

[1] The tip-link antigen, a protein associated with the transduction complex of sensory hair cells, is protocadherin-15 [J].