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NMR structure of the LCCL domain and implications for DFNA9 deafness disorder
Author(s) -
Liepinsh Edvards,
Trexler Mária,
Kaikkonen Andrei,
Weigelt Johan,
Bányai László,
Patthy László,
Otting Gottfried
Publication year - 2001
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/20.19.5347
Subject(s) - mutant , protein folding , biology , folding (dsp implementation) , protein domain , limulus , mutation , protein structure , crystallography , biophysics , genetics , microbiology and biotechnology , gene , biochemistry , chemistry , evolutionary biology , engineering , electrical engineering
The LCCL domain is a recently discovered, conserved protein module named after its presence in Limulus factor C, cochlear protein Coch‐5b2 and late gestation lung protein Lgl1. The LCCL domain plays a key role in the autosomal dominant human deafness disorder DFNA9. Here we report the nuclear magnetic resonance (NMR) structure of the LCCL domain from human Coch‐5b2, where dominant mutations leading to DFNA9 deafness disorder have been identified. The fold is novel. Four of the five known DFNA9 mutations are shown to involve at least partially solvent‐exposed residues. Except for the Trp91Arg mutant, expression of these four LCCL mutants resulted in misfolded proteins. These results suggest that Trp91 participates in the interaction with a binding partner. The unexpected sensitivity of the fold with respect to mutations of solvent‐accessible residues might be attributed to interference with the folding pathway of this disulfide‐containing domain.