Dataset Information

GIPC3 couples to MYO6 and PDZ domain proteins and shapes the hair cell apical region.

ABSTRACT: GIPC3 has been implicated in auditory function. Initially localized to the cytoplasm of inner and outer hair cells of the cochlea, GIPC3 increasingly concentrated in cuticular plates and at cell junctions during postnatal development. Early postnatal Gipc3 ^KO/KO mice had mostly normal mechanotransduction currents, but had no auditory brainstem response at one month of age. Cuticular plates of Gipc3 ^KO/KO hair cells did not flatten during development as did those of controls; moreover, hair bundles were squeezed along the cochlear axis in mutant hair cells. Junctions between inner hair cells and adjacent inner phalangeal cells were also severely disrupted in Gipc3 ^KO/KO cochleas. GIPC3 bound directly to MYO6, and the loss of MYO6 led to altered distribution of GIPC3. Immunoaffinity purification of GIPC3 from chicken inner ear extracts identified co-precipitating proteins associated with adherens junctions, intermediate filament networks, and the cuticular plate. Several of immunoprecipitated proteins contained GIPC-family consensus PDZ binding motifs (PBMs), including MYO18A, which binds directly to the PDZ domain of GIPC3. We propose that GIPC3 and MYO6 couple to PBMs of cytoskeletal and cell-junction proteins to shape the cuticular plate.

Summary statement

The PDZ-domain protein GIPC3 couples the molecular motors MYO6 and MYO18A to actin cytoskeleton structures in hair cells. GIPC3 is necessary for shaping the hair cellâ€™s cuticular plate and hence the arrangement of the stereocilia in the hair bundle.

SUBMITTER: Chatterjee P

PROVIDER: S-EPMC10002731 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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GIPC3 couples to MYO6 and PDZ domain proteins and shapes the hair cell apical region.

Chatterjee Paroma P Morgan Clive P CP Krey Jocelyn F JF Benson Connor C Goldsmith Jennifer J Bateschell Michael M Ricci Anthony J AJ Barr-Gillespie Peter G PG

bioRxiv : the preprint server for biology 20230301

GIPC3 has been implicated in auditory function. Initially localized to the cytoplasm of inner and outer hair cells of the cochlea, GIPC3 increasingly concentrated in cuticular plates and at cell junctions during postnatal development. Early postnatal Gipc3 KO/KO mice had mostly normal mechanotransduction currents, but had no auditory brainstem response at one month of age. Cuticular plates of Gipc3 KO/KO hair cells did not flatten during development as did tho ...[more]

PMID: 36909580

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Project description:BACKGROUND: Schistosomiasis is a serious global health problem that afflicts more than 230 million people in 77 countries. Long-term mass treatments with the only available drug, praziquantel, have caused growing concerns about drug resistance. PSD-95/Dlg/ZO-1 (PDZ) domain-containing proteins are recognized as potential targets for the next generation of drug development. However, the PDZ domain-containing protein family in parasites has largely been unexplored. METHODS: We present the molecular characteristics of a PDZ domain-containing protein, GIPC3, from Schistosoma japonicum (SjGIPC3) according to bioinformatics analysis and experimental approaches. The ligand binding specificity of the PDZ domain of SjGIPC3 was confirmed by screening an arbitrary peptide library in yeast two-hybrid (Y2H) assays. The native ligand candidates were predicted by Tailfit software based on the C-terminal binding specificity, and further validated by Y2H assays. RESULTS: SjGIPC3 is a single PDZ domain-containing protein comprised of 328 amino acid residues. Structural prediction revealed that a conserved PDZ domain was presented in the middle region of the protein. Phylogenetic analysis revealed that SjGIPC3 and other trematode orthologues clustered into a well-defined cluster but were distinguishable from those of other phyla. Transcriptional analysis by quantitative RT-PCR revealed that the SjGIPC3 gene was relatively highly expressed in the stages within the host, especially in male adult worms. By using Y2H assays to screen an arbitrary peptide library, we confirmed the C-terminal binding specificity of the SjGIPC3-PDZ domain, which could be deduced as a consensus sequence, -[SDEC]-[STIL]-[HSNQDE]-[VIL]*. Furthermore, six proteins were predicted to be native ligand candidates of SjGIPC3 based on the C-terminal binding properties and other biological information; four of these were confirmed to be potential ligands using the Y2H system. CONCLUSIONS: In this study, we first characterized a PDZ domain-containing protein GIPC3 in S. japonicum. The SjGIPC3-PDZ domain is able to bind both type I and II ligand C-terminal motifs. The identification of native ligand will help reveal the potential biological function of SjGIPC3. These data will facilitate the identification of novel drug targets against S. japonicum infections.

Dataset Information

GIPC3 couples to MYO6 and PDZ domain proteins and shapes the hair cell apical region.

Summary statement

Publications

GIPC3 couples to MYO6 and PDZ domain proteins and shapes the hair cell apical region.

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