Document Detail

The structure of the harmonin/sans complex reveals an unexpected interaction mode of the two Usher syndrome proteins.
MedLine Citation:
PMID:  20142502     Owner:  NLM     Status:  MEDLINE    
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.
Jing Yan; Lifeng Pan; Xiuye Chen; Lin Wu; Mingjie Zhang
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-02-08
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  107     ISSN:  1091-6490     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2010 Mar 
Date Detail:
Created Date:  2010-03-03     Completed Date:  2010-04-16     Revised Date:  2013-05-31    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4040-5     Citation Subset:  IM    
Department of Biochemistry, Molecular Neuroscience Center, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong.
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MeSH Terms
Adaptor Proteins, Signal Transducing / chemistry,  genetics,  metabolism*
Models, Molecular
Nerve Tissue Proteins / chemistry,  genetics,  metabolism*
Protein Binding
Protein Conformation
Usher Syndromes / metabolism*
Reg. No./Substance:
0/Adaptor Proteins, Signal Transducing; 0/Nerve Tissue Proteins; 0/USH1C protein, human; 0/USH1G protein, human

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