♦ See referenced article, J. Biol. Chem. 2016, 291, 3124–3134
Legius syndrome is a condition where skin coloring changes in patches. Individuals have multiple café-au-lait spots that are darker than the surrounding area. Mutations in the SPRED1 gene have been implicated in Legius syndrome. Many Legius syndrome signs and symptoms also occur in a similar disorder called neurofibromatosis type 1 (NF1). Mutations in the NF1 gene, which makes neurofibromin, have been identified in neurofibromatosis type 1. Researchers know that SPRED1 interacts with NF1, but the details of the interaction are unknown. In this Paper of the Week, a team led by Akihiko Yoshimura at Keio University School of Medicine in Japan used yeast two-hybrid screens and immunoprecipitation assays to determine that a domain in SPRED1 interacts with the GTPase-activating protein-related domain (GRD) of neurofibromin. From the data, the investigators determined that this interaction leads to the inhibition of protooncogenic Ras-ERK pathway by SPRED1 because it recruits neurofibromin to Ras. The authors say, “This study also provides molecular basis for the pathogenic mutations of NF1 and Legius syndrome.”
An in silico modeling of the interaction between the SPRED1 domain and the GRD domain of neurofibromin.