title: An elastic element in the protocadherin-15 tip link of the inner ear.
abstract: Tip link filaments convey force and gate inner-ear hair-cell transduction channels to mediate perception of sound and head movements. Cadherin-23 and protocadherin-15 form tip links through a calcium-dependent interaction of their extracellular domains made of multiple extracellular cadherin (EC) repeats. These repeats are structurally similar, but not identical in sequence, often featuring linkers with conserved calcium-binding sites that confer mechanical strength to them. Here we present the X-ray crystal structures of human protocadherin-15 EC8-EC10 and mouse EC9-EC10, which show an EC8-9 canonical-like calcium-binding linker, and an EC9-10 calcium-free linker that alters the linear arrangement of EC repeats. Molecular dynamics simulations and small-angle X-ray scattering experiments support this non-linear conformation. Simulations also suggest that unbending of EC9-10 confers some elasticity to otherwise rigid tip links. The new structure provides a first view of protocadherin-15's non-canonical EC linkers and suggests how they may function in inner-ear mechanotransduction, with implications for other cadherins.
authors.affiliation: Department of Chemistry and Biochemistry, The Ohio State University, 484 W 12th Avenue, Columbus, Ohio 43210, USA.
authors.forename: Raul
authors.identifier: 0000-0002-4872-3553
authors.initials: R
authors.lastname: Araya-Secchi
authors.affiliation: Department of Chemistry and Biochemistry, The Ohio State University, 484 W 12th Avenue, Columbus, Ohio 43210, USA.
authors.forename: Brandon L
authors.initials: BL
authors.lastname: Neel
authors.affiliation: Department of Chemistry and Biochemistry, The Ohio State University, 484 W 12th Avenue, Columbus, Ohio 43210, USA.
authors.forename: Marcos
authors.identifier: 0000-0002-3333-1805
authors.initials: M
authors.lastname: Sotomayor
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000070585:Cadherin Related Proteins; D015820:Cadherins / Q000737:chemistry / Q000378:metabolism*; D003198:Computer Simulation; D006199:Hair Cells, Auditory, Inner / Q000502:physiology*; D006801:Humans; D040542:Mechanotransduction, Cellular / Q000502:physiology; D051379:Mice; D008954:Models, Biological; D008958:Models, Molecular; D011487:Protein Conformation; D011498:Protein Precursors / Q000737:chemistry / Q000378:metabolism*
chemical_list: C418976:CDHR15 protein, mouse; C498835:CDHR15, human; D000070585:Cadherin Related Proteins; D015820:Cadherins; D011498:Protein Precursors