NMR structure of the LCCL domain and implications for DFNA9 deafness disorder.
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.
Liepinsh
E
E
Department of Medical Biochemistry and Biophysics, Karolinska Institute, 17177 Stockholm, Sweden.
Trexler
M
M
Kaikkonen
A
A
Weigelt
J
J
Bányai
L
L
Patthy
L
L
Otting
G
G
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
C110668:COCH protein, human; D016326:Extracellular Matrix Proteins; D011506:Proteins