Francesca Fanelli and Michele Seeber
ABSTRACT Disease-causing missense mutations in membrane proteins, such as rhodopsin mutations asso- ciated with the autosomal dominant form of retinitis pigmentosa (ADRP), are often linked to defects in folding and/or trafficking. The mechanical unfolding of wild-type rhodopsin was compared with that of 20 selected ADRP-linked mutants more or less defective in folding and retinal binding. Rhodopsin fold is charac- terized by networks of amino acids in the retinal and G-protein binding sites likely to play a role in the stability and function of the protein. The distribution of highly connected nodes in the network reflects the existence of a diffuse intramolecular communication inside and between the 2 poles of the helix bundle, which makes pathogenic mutations share similar phe- notypes irrespective of topological and physicochemi- cal differences between them. Because of this commu- nication, the ADRP-linked rhodopsin mutations share a more or less marked ability to impair selected hubs in the protein structure network. The extent of this struc- tural effect relates to the severity of the biochemical defect caused by mutation. The investigative strategy employed in this study is likely to apply to all structur- ally known membrane proteins particularly susceptible to misassembly-causing mutations.
Fanelli, F., Seeber, M. Structural insights into retinitis pigmentosa from unfolding simulations of rhodopsin mutants. FASEB J. 24, 3196-3209 (2010). www.fasebj.org