Cadherin 23-C Regulates Microtubule Networks by Modifying CAMSAP3's Function

Sci Rep. 2016 Jun 28:6:28706. doi: 10.1038/srep28706.

Abstract

Cadherin-related 23 (CDH23) is an adhesive protein important for hearing and vision, while CAMSAP3/Marshalin is a microtubule (MT) minus-end binding protein that regulates MT networks. Although both CDH23 and CAMSAP3/Marshalin are expressed in the organ of Corti, and carry several protein-protein interaction domains, no functional connection between these two proteins has been proposed. In this report, we demonstrate that the C isoform of CDH23 (CDH23-C) directly binds to CAMSAP3/Marshalin and modifies its function by inhibiting CAMSAP3/Marshalin-induced bundle formation, a process that requires a tubulin-binding domain called CKK. We further identified a conserved N-terminal region of CDH23-C that binds to the CKK domain. This CKK binding motif (CBM) is adjacent to the domain that interacts with harmonin, a binding partner of CDH23 implicated in deafness. Because the human Usher Syndrome 1D-associated mutation, CDH23 R3175H, maps to the CBM, we created a matched mutation in mouse CDH23-C at R55H. Both in vivo and in vitro assays decreased the ability of CDH23-C to interact with CAMSAP3/Marshalin, indicating that the interaction between CDH23 and CAMSAP3/Marshalin plays a vital role in hearing and vision. Together, our data suggest that CDH23-C is a CAMSAP3/Marshalin-binding protein that can modify MT networks indirectly through its interaction with CAMSAP3/Marshalin.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Substitution
  • Animals
  • Cadherin Related Proteins
  • Cadherins* / chemistry
  • Cadherins* / genetics
  • Cadherins* / metabolism
  • Cell Line
  • Humans
  • Mice
  • Microtubule-Associated Proteins* / chemistry
  • Microtubule-Associated Proteins* / genetics
  • Microtubule-Associated Proteins* / metabolism
  • Microtubules* / chemistry
  • Microtubules* / genetics
  • Microtubules* / metabolism
  • Mutation, Missense

Substances

  • CDH23 protein, human
  • Cadherin Related Proteins
  • Cadherins
  • Camsap3 protein, human
  • Camsap3 protein, mouse
  • Cdh23 protein, mouse
  • Microtubule-Associated Proteins