Report

Structure of the Integral Membrane Protein CAAX Protease Ste24p

Science  29 Mar 2013:
Vol. 339, Issue 6127, pp. 1600-1604
DOI: 10.1126/science.1232048

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Lamin Loppers

The nuclear lamina provides mechanical stability to the nuclear envelope and is involved in regulation of cellular processes such as DNA replication. Defects in the nuclear lamina lead to diseases such as progeria and metabolic disorders. One of the components of the nuclear lamina, lamin A, undergoes a complex maturation process. A key player is an inner nuclear membrane zinc metalloprotease (ZMP) that is responsible for two proteolysis steps (see the Perspective by Michaelis and Hrycyna). Quigley et al. (p. 1604) report the crystal structure of human ZMPSTE24 and Pryor et al. (p. 1600) that of the yeast homolog Ste24p. The structures provide insight into the mechanism of catalysis and into why mutations in ZMPSTE24 lead to laminopathies.

Abstract

Posttranslational lipidation provides critical modulation of the functions of some proteins. Isoprenoids (i.e., farnesyl or geranylgeranyl groups) are attached to cysteine residues in proteins containing C-terminal CAAX sequence motifs (where A is an aliphatic residue and X is any residue). Isoprenylation is followed by cleavage of the AAX amino acid residues and, in some cases, by additional proteolytic cuts. We determined the crystal structure of the CAAX protease Ste24p, a zinc metalloprotease catalyzing two proteolytic steps in the maturation of yeast mating pheromone a-factor. The Ste24p core structure is a ring of seven transmembrane helices enclosing a voluminous cavity containing the active site and substrate-binding groove. The cavity is accessible to the external milieu by means of gaps between splayed transmembrane helices. We hypothesize that cleavage proceeds by means of a processive mechanism of substrate insertion, translocation, and ejection.

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