PerspectiveBiochemistry

A Protease for the Ages

See allHide authors and affiliations

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

You are currently viewing the summary.

View Full Text

Log in to view the full text

Log in through your institution

Log in through your institution

Summary

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.