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Signal transduction is the process of converting one kind of signal or stimulus into another, with the goal of processing external or internal signals into diverse functions. In recent years, progress has been made in identifying signaling pathways, investigating cross-talk and feedbacks in signaling modules, analyzing cell-type specific signaling, and unraveling spatial-temporal aspects, such as receptor clustering into micro-domains, dynamic localization, and mathematical modeling. Here, we used the receptor/MAPK signaling system as an example, and we discuss the current and remaining challenges: the role of scaffolds and signaling machines, the importance of concentration and competition, the use of structural information, the integration of large-scale proteomic datasets, and the future challenge of integrating alternative splicing into signaling pathways., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Retinitis pigmentosa (RP) refers to a heterogeneous group of inherited diseases that result in progressive retinal degeneration, characterized by visual field constriction and night blindness. A total of 103 mutations in rhodopsin are linked to RP to date, and the phenotypes range from severe to asymptomatic. To study the relation between phenotype and rhodopsin stability in disease mutants, we used a structure-based approach. For 12 of the mutants located at the protein-lipid interphase, we used the von Heijne water-membrane transfer scale, and we find that 9 of the mutations could affect membrane insertion. For 91 mutants, we used the protein design algorithm FoldX. The 3 asymptomatic mutations had no significant reduced stability, 2 were unsuitable for FoldX analysis since the structure was incorrect in this region, 63 mutations had a significant change in protein stability (>1.6 kcal/mol), and 23 mutations had energy change values under the prediction error threshold (<1.6 kcal/mol). Out of these 23, the disease-causing effect could be explained by the involvement in other functions (e.g., glycosylation motifs, the interface with arrestin and transducin, and the cilia-binding motif) for 19 mutants. The remaining 4 mutants were probably incorrectly associated with RP or have functionalities not discovered yet. For destabilizing mutations where clinical data were available, we found a highly significant correlation between FoldX energy changes and the average age of night blindness and between FoldX energy changes and daytime vision loss onset. Our detailed structural, functional, and energetic analysis provides a complete picture of the rhodopsin mutations and can guide mutation-specific therapies., (Copyright © 2010 Elsevier Ltd. All rights reserved.)