7DE7

Crystal structure of PDZD7 HHD domain

Summary for 7DE7

• Entry DOI: 10.2210/pdb7de7/pdb
• Descriptor: PDZ domain-containing protein 7, (2R)-2-{[(2R)-2-{[(2S)-2-{[(2R)-2-hydroxypropyl]oxy}propyl]oxy}propyl]oxy}propan-1-ol (3 entities in total)
• Functional Keywords: pdzd7, hhd domain, membrane-targeting, lipid binding protein
• Biological source: Mus musculus (Mouse)
• Total number of polymer chains: 2
• Total formula weight: 23773.40

Authors

Wang, H.,Lin, L.,Lu, Q. (deposition date: 2020-11-02, release date: 2021-08-25, Last modification date: 2023-11-29)

Primary citation

Lin, L.,Wang, H.,Ren, D.,Xia, Y.,He, G.,Lu, Q.
Structure and Membrane Targeting of the PDZD7 Harmonin Homology Domain (HHD) Associated With Hearing Loss.
Front Cell Dev Biol, 9:642666-642666, 2021

PubMed Abstract: Usher syndrome (USH) is the leading cause of hereditary hearing-vision loss in humans. PDZ domain-containing 7 (PDZD7) has been reported to be a modifier of and contributor to USH. PDZD7 co-localizes with USH2 proteins in the inner ear hair cells and is essential for ankle-link formation and stereocilia development. PDZD7 contains three PDZ domains and a low-complexity region between the last two PDZ domains, which has been overlooked in the previous studies. Here we characterized a well-folded harmonin homology domain (HHD) from the middle region and solved the PDZD7 HHD structure at the resolution of 1.49 Å. PDZD7 HHD adopts the same five-helix fold as other HHDs found in Harmonin and Whirlin; however, in PDZD7 HHD, a unique α1N helix occupies the canonical binding pocket, suggesting a distinct binding mode. Moreover, we found that the PDZD7 HHD domain can bind lipid and mediate the localization of PDZD7 to the plasma membrane in HEK293T cells. Intriguingly, a hearing-loss mutation at the N-terminal extension region of the HHD can disrupt the lipid-binding ability of PDZD7 HHD, suggesting that HHD-mediated membrane targeting is required for the hearing process. This structural and biochemical characterization of the PDZD7 HHD region provides mechanistic explanations for human deafness-causing mutations in PDZD7. Furthermore, this structure will also facilitate biochemical and functional studies of other HHDs.

PubMed: 33937240
DOI: 10.3389/fcell.2021.642666

Experimental method

X-RAY DIFFRACTION (1.49 Å)