title: Interactions in the network of Usher syndrome type 1 proteins.
abstract: Defects in myosin VIIa, harmonin (a PDZ domain protein), cadherin 23, protocadherin 15 and sans (a putative scaffolding protein), underlie five forms of Usher syndrome type I (USH1). Mouse mutants for all these proteins exhibit disorganization of their hair bundle, which is the mechanotransduction receptive structure of the inner ear sensory cells, the cochlear and vestibular hair cells. We have previously demonstrated that harmonin interacts with cadherin 23 and myosin VIIa. Here we address the extent of interactions between the five known USH1 proteins. We establish the previously suggested sans-harmonin interaction and find that sans also binds to myosin VIIa. We show that sans can form homomeric structures and that harmonin b can interact with all harmonin isoforms. We reveal that harmonin also binds to protocadherin 15. Molecular characterization of these interactions indicates that through its binding to four of the five USH1 proteins, the first PDZ domain (PDZ1) of harmonin plays a central role in this network. We localize sans in the apical region of cochlear and vestibular hair cell bodies underneath the cuticular plate. In contrast to the other four known USH1 proteins, no sans labeling was detected within the stereocilia. We propose that via its binding to myosin VIIa and/or harmonin, sans controls the hair bundle cohesion and proper development by regulating the traffic of USH1 proteins en route to the stereocilia.
authors.affiliation: Unité de Génétique des Déficits Sensoriels, INSERM U587, Institut Pasteur, 25 rue du Dr Roux, 75724 Paris cedex 15, France.
authors.forename: Avital
authors.initials: A
authors.lastname: Adato
authors.forename: Vincent
authors.initials: V
authors.lastname: Michel
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kikkawa
authors.forename: Jan
authors.initials: J
authors.lastname: Reiners
authors.forename: Kumar N
authors.initials: KN
authors.lastname: Alagramam
authors.forename: Dominique
authors.initials: D
authors.lastname: Weil
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Yonekawa
authors.forename: Uwe
authors.initials: U
authors.lastname: Wolfrum
authors.forename: Aziz
authors.initials: A
authors.lastname: El-Amraoui
authors.forename: Christine
authors.initials: C
authors.lastname: Petit
mesh_terms: D000818:Animals; D000070585:Cadherin Related Proteins; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; D004398:Dyneins / Q000235:genetics / Q000378:metabolism*; D006198:Hair Cells, Auditory / Q000166:cytology / Q000378:metabolism; D006367:HeLa Cells; D006319:Hearing Loss, Sensorineural / Q000235:genetics; D006801:Humans; D051379:Mice; D009154:Mutation; D000081412:Myosin VIIa; D009218:Myosins / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism*; D012174:Retinitis Pigmentosa / Q000235:genetics; D013577:Syndrome; D020798:Two-Hybrid System Techniques
chemical_list: C442480:CDH23 protein, human; C418976:CDHR15 protein, mouse; C498835:CDHR15, human; D000070585:Cadherin Related Proteins; D015820:Cadherins; D002352:Carrier Proteins; C499091:Cdh23 protein, mouse; D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; C000631455:MYO7A protein, human; C000631456:Myo7a protein, mouse; D000081412:Myosin VIIa; D009419:Nerve Tissue Proteins; D011498:Protein Precursors; C477451:Sans protein, mouse; C492262:Ush1c protein, mouse; D009218:Myosins; D004398:Dyneins