3K1R

Structure of harmonin NPDZ1 in complex with the SAM-PBM of Sans

Summary for 3K1R

• Entry DOI: 10.2210/pdb3k1r/pdb
• Related: 2KBQ 2KBR
• Descriptor: Harmonin, Usher syndrome type-1G protein (3 entities in total)
• Functional Keywords: protein-protein complex, alternative splicing, coiled coil, deafness, hearing, non-syndromic deafness, polymorphism, retinitis pigmentosa, sensory transduction, usher syndrome, vision, ank repeat, disease mutation, structural protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 30379.05

Authors

Pan, L.,Yan, J.,Zhang, M. (deposition date: 2009-09-28, release date: 2010-01-26, Last modification date: 2023-11-01)

Primary citation

Yan, J.,Pan, L.,Chen, X.,Wu, L.,Zhang, M.
The structure of the harmonin/sans complex reveals an unexpected interaction mode of the two Usher syndrome proteins
Proc.Natl.Acad.Sci.USA, 107:4040-4045, 2010

PubMed Abstract: The hereditary hearing-vision loss disease, Usher syndrome I (USH1), is caused by defects in several proteins that can interact with each other in vitro. Defects in USH1 proteins are thought to be responsible for the developmental and functional impairments of sensory cells in the retina and inner ear. Harmonin/USH1C and Sans/USH1G are two of the USH1 proteins that interact with each other. Harmonin also binds to other USH1 proteins such as cadherin 23 (CDH23) and protocadherin 15 (PCDH15). However, the molecular basis governing the harmonin and Sans interaction is largely unknown. Here, we report an unexpected assembly mode between harmonin and Sans. We demonstrate that the N-terminal domain and the first PDZ domain of harmonin are tethered by a small-domain C-terminal to PDZ1 to form a structural and functional supramodule responsible for binding to Sans. We discover that the SAM domain of Sans, specifically, binds to the PDZ domain of harmonin, revealing previously unknown interaction modes for both PDZ and SAM domains. We further show that the synergistic PDZ1/SAM and PDZ1/carboxyl PDZ binding-motif interactions, between harmonin and Sans, lock the two scaffold proteins into a highly stable complex. Mutations in harmonin and Sans found in USH1 patients are shown to destabilize the complex formation of the two proteins.

PubMed: 20142502
DOI: 10.1073/pnas.0911385107

Experimental method

X-RAY DIFFRACTION (2.3 Å)