Interactions in the network of Usher syndrome type 1 proteins

• Published in: Human molecular genetics 2005-02, Vol.14 (3), p.347-356
• Main Authors: Adato, Avital, Michel, Vincent, Kikkawa, Yoshiaki, Reiners, Jan, Alagramam, Kumar N., Weil, Dominique, Yonekawa, Hiromichi, Wolfrum, Uwe, El-Amraoui, Aziz, Petit, Christine
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Cadherins - genetics; Cadherins - metabolism; Carrier Proteins - genetics; Carrier Proteins - metabolism; Dyneins - genetics; Dyneins - metabolism; Fundamental and applied biological sciences. Psychology; Genetics of eukaryotes. Biological and molecular evolution; Hair Cells, Auditory - cytology; Hair Cells, Auditory - metabolism; Hearing Loss, Sensorineural - genetics; HeLa Cells; Humans; Life Sciences; Medical sciences; Mice; Molecular and cellular biology; Mutation; Myosins - genetics; Myosins - metabolism; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Ophthalmology; Protein Binding; Protein Precursors - genetics; Protein Precursors - metabolism; Retinitis Pigmentosa - genetics; Retinopathies; Syndrome; Two-Hybrid System Techniques
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddi031

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.