A Protease for the Ages

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Science  29 Mar 2013:
Vol. 339, Issue 6127, pp. 1529-1530
DOI: 10.1126/science.1236764

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Mutations in the genes encoding the nuclear scaffold protein lamin A or the zinc metalloprotease ZMPSTE24 cause the devastating premature aging disorder Hutchinson-Guilford progeria syndrome (HGPS) and the related progeroid disorders restrictive dermopathy (RD) and mandibuloacral dysplasia (MAD-B) (14). Children with HGPS, for example, manifest accelerated aging symptoms, including failure to thrive, hair loss, joint ailments, lipodystrophy, and cardiovascular disease, typically dying from the latter in their mid-teens. In all of these progeroid disorders, a persistently farnesylated and methylated form of lamin A is the “molecular culprit,” exerting dominant-negative effects that promote aging-related symptoms (1). On pages 1604 and 1600 of this issue, Quigley et al. (5) and Pryor et al. (6) report the three-dimensional crystal structures of the human zinc metallo-protease ZMPSTE24 and its yeast homolog, Ste24p. These proteases play critical roles in two steps of the posttranslational maturation of human lamin A and the yeast mating pheromone a-factor, respectively (79). ZMPSTE24 and Ste24p are multispanning membrane proteins and as such, determining their structures by x-ray crystallography represents a substantial accomplishment. The structures should lead to a better understanding of how these enzymes function and how they are associated with aging.