NMR structure of the LCCL domain and implications for DFNA9 deafness disorder

The LCCL domain is a recently discovered, conserved protein module named af ter its presence in Limulus factor C, cochlear protein Coch-5b2 and late ge station lung protein Lgl1. The LCCL domain plays a key role in the autosoma l dominant human deafness disorder DFNA9. Here we report the nuclear magnet ic 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 inv olve at least partially solvent-exposed residues. Except for the Trp91Arg m utant, expression of these four LCCL mutants resulted in misfolded proteins . These results suggest that Trp91 participates in the interaction with a b inding partner. The unexpected sensitivity of the fold with respect to muta tions of solvent-accessible residues might be attributed to interference wi th the folding pathway of this disulfide-containing domain.