title: NMR structure of the LCCL domain and implications for DFNA9 deafness disorder.
abstract: 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.
authors.affiliation: Department of Medical Biochemistry and Biophysics, Karolinska Institute, 17177 Stockholm, Sweden.
authors.forename: E
authors.initials: E
authors.lastname: Liepinsh
authors.forename: M
authors.initials: M
authors.lastname: Trexler
authors.forename: A
authors.initials: A
authors.lastname: Kaikkonen
authors.forename: J
authors.initials: J
authors.lastname: Weigelt
authors.forename: L
authors.initials: L
authors.lastname: Bányai
authors.forename: L
authors.initials: L
authors.lastname: Patthy
authors.forename: G
authors.initials: G
authors.lastname: Otting
mesh_terms: D000595:Amino Acid Sequence; D017124:Conserved Sequence; D003638:Deafness / Q000235:genetics*; D016326:Extracellular Matrix Proteins; D006319:Hearing Loss, Sensorineural / Q000235:genetics*; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry* / Q000235:genetics*; D017386:Sequence Homology, Amino Acid
chemical_list: C110668:COCH protein, human; D016326:Extracellular Matrix Proteins; D011506:Proteins