Human Molecular Genetics Advance Access published online on September 28, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm285
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A novel Usher protein network at the periciliary reloading point between molecular transport machineries in vertebrate photoreceptor cells
1 Department of Cell and Matrix Biology, Institute of Zoology, Johannes Gutenberg University of Mainz, 55099 Mainz, Germany 2 Department of Otorhinolaryngology, Radboud University Nijmegen Medical Centre, Nijmegen Centre for Molecular Life Sciences, 6500 HB Nijmegen, The Netherlands 3 Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen Centre for Molecular Life Sciences, 6500 HB Nijmegen, The Netherlands 4 Department of Ophthalmology, Radboud University Nijmegen Medical Centre, Radboud University, Nijmegen Medical Centre, Nijmegen Centre for Molecular Life Sciences, 6500 HB Nijmegen, The Netherlands 5 Nijmegen Centre for Molecular Life Sciences, 6500 HB Nijmegen, The Netherlands 6 Developmental Auditory Physiology Laboratory, Boys Town National Research Hospital, Omaha, Nebraska 68131, U.S.A
* Corresponding author: Uwe Wolfrum, Johannes Gutenberg University Mainz, Institute of Zoology, Department of Cell and Matrix Biology, Muellerweg 6, D-55099 Mainz, Germany. Tel.: +49-6131-39-25148; Fax: +49-6131-39-23815; E-mail: wolfrum{at}uni-mainz.de
Received August 21, 2007; Revised September 27, 2007; Accepted September 27, 2007
The human Usher syndrome (USH) is the most frequent cause of combined deaf-blindness. USH is genetically heterogeneous with at least 12 chromosomal loci assigned to three clinical types, USH1-3. Although these USH types exhibit similar phenotypes in human, the corresponding gene products belong to very different protein classes and families.
The scaffold protein harmonin (USH1C) was shown to integrate all identified USH1 and USH2 molecules into protein networks. Here, we analyzed a protein network organized in the absence of harmonin by the scaffold proteins SANS (USH1G) and whirlin (USH2D). Immunoelectron microscopic analyses disclosed the colocalization of all network components in the apical inner segment collar and the ciliary apparatus of mammalian photoreceptor cells. In this complex, whirlin and SANS directly interact. Furthermore, SANS provides a linkage to the microtubule transport machinery, whereas whirlin may anchor USH2A isoform b and VLGR1b via binding to their cytodomains at specific membrane domains. The long ectodomains of both transmembrane proteins extend into the gap between the adjacent membranes of the connecting cilium and the apical inner segment. Analyses of Vlgr1/del7TM mice revealed the ectodomain of VLGR1b as a component of fibrous links present in this gap. Comparative analyses of mouse and Xenopus photoreceptors demonstrated that this USH protein network is also part of the periciliary ridge complex in Xenopus. Since this structural specialization in amphibian photoreceptor cells defines a specialized membrane domain for docking and fusion of transport vesicles, we suggest a prominent role of the USH proteins in cargo shipment.
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