Structural highlights
Disease
[PCD15_MOUSE] Defects in Pcdh15 are the cause of the Ames waltzer (av) phenotype. It is characterized by deafness and a balance disorder, associated with the degeneration of inner ear neuroepithelia. [LHPL5_MOUSE] Defects in Lhfpl5 are the cause of the hurry-scurry (hscy) phenotype which is characterized by rapid circling behavior, frequent shaking of head from side to side, deafness and vestibular dysfunction.[1]
Function
[PCD15_MOUSE] Calcium-dependent cell-adhesion protein. Required for inner ear neuroepithelial cell elaboration and cochlear function. Probably involved in the maintenance of normal retinal function. [LHPL5_MOUSE] In the inner ear, may be a component of the hair cell's mechanotransduction machinery that functionally couples PCDH15 to the transduction channel. Regulates transducer channel conductance and is required for fast channel adaptation.[2] [3]
Publication Abstract from PubMed
Hearing and balance involve the transduction of mechanical stimuli into electrical signals by deflection of bundles of stereocilia linked together by protocadherin 15 (PCDH15) and cadherin 23 'tip links'. PCDH15 transduces tip link tension into opening of a mechano-electrical transduction (MET) ion channel. PCDH15 also interacts with LHFPL5, a candidate subunit of the MET channel. Here we illuminate the PCDH15-LHFPL5 structure, showing how the complex is composed of PCDH15 and LHFPL5 subunit pairs related by a 2-fold axis. The extracellular cadherin domains define a mobile tether coupled to a rigid, 2-fold symmetric 'collar' proximal to the membrane bilayer. LHFPL5 forms extensive interactions with the PCDH15 transmembrane helices and stabilizes the overall PCDH15-LHFPL5 assembly. Our studies illuminate the architecture of the PCDH15-LHFPL5 complex, localize mutations associated with deafness, and shed new light on how forces in the PCDH15 tether may be transduced into the stereocilia membrane.
Structure of mouse protocadherin 15 of the stereocilia tip link in complex with LHFPL5.,Ge J, Elferich J, Goehring A, Zhao H, Schuck P, Gouaux E Elife. 2018 Aug 2;7. pii: 38770. doi: 10.7554/eLife.38770. PMID:30070639[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Longo-Guess CM, Gagnon LH, Cook SA, Wu J, Zheng QY, Johnson KR. A missense mutation in the previously undescribed gene Tmhs underlies deafness in hurry-scurry (hscy) mice. Proc Natl Acad Sci U S A. 2005 May 31;102(22):7894-9. doi:, 10.1073/pnas.0500760102. Epub 2005 May 19. PMID:15905332 doi:http://dx.doi.org/10.1073/pnas.0500760102
- ↑ Longo-Guess CM, Gagnon LH, Cook SA, Wu J, Zheng QY, Johnson KR. A missense mutation in the previously undescribed gene Tmhs underlies deafness in hurry-scurry (hscy) mice. Proc Natl Acad Sci U S A. 2005 May 31;102(22):7894-9. doi:, 10.1073/pnas.0500760102. Epub 2005 May 19. PMID:15905332 doi:http://dx.doi.org/10.1073/pnas.0500760102
- ↑ Xiong W, Grillet N, Elledge HM, Wagner TF, Zhao B, Johnson KR, Kazmierczak P, Muller U. TMHS is an integral component of the mechanotransduction machinery of cochlear hair cells. Cell. 2012 Dec 7;151(6):1283-95. doi: 10.1016/j.cell.2012.10.041. PMID:23217710 doi:http://dx.doi.org/10.1016/j.cell.2012.10.041
- ↑ Ge J, Elferich J, Goehring A, Zhao H, Schuck P, Gouaux E. Structure of mouse protocadherin 15 of the stereocilia tip link in complex with LHFPL5. Elife. 2018 Aug 2;7. pii: 38770. doi: 10.7554/eLife.38770. PMID:30070639 doi:http://dx.doi.org/10.7554/eLife.38770
