ZMPSTE24 is a zinc metalloproteinase enzyme in humans encoded by the ZMPSTE24 gene. It is also known as FACE1 (farnesylated cell transformation gene, exon 1 product) and Ste24 endopeptidase. This enzyme plays a critical role in the post-translational processing of prelamin A, a precursor to lamin A, a protein essential for the structure and function of the nuclear lamina.
The nuclear lamina is a protein meshwork that lines the inner surface of the nuclear envelope in eukaryotic cells. Lamin A, along with lamin B and lamin C, provides structural support to the nucleus, regulates gene expression, and participates in DNA replication and repair.
Prelamin A undergoes a series of modifications, including farnesylation, carboxymethylation, and endoproteolytic cleavage, to become mature lamin A. ZMPSTE24 specifically catalyzes the final cleavage step, removing the farnesylated C-terminal amino acids of prelamin A. This cleavage is essential for the proper incorporation of lamin A into the nuclear lamina.
Mutations in the ZMPSTE24 gene can lead to a variety of genetic disorders, collectively known as laminopathies. These disorders are often characterized by premature aging (progeria) and skeletal abnormalities. The most well-known condition associated with ZMPSTE24 mutations is Hutchinson-Gilford progeria syndrome (HGPS), although the majority of HGPS cases are caused by mutations in the LMNA gene, which encodes prelamin A. In cases of ZMPSTE24-related progeria, the impaired cleavage of prelamin A results in the accumulation of unprocessed prelamin A in the nuclear lamina, disrupting nuclear structure and function, and ultimately leading to cellular dysfunction and premature aging. Other disorders linked to ZMPSTE24 mutations include Mandibuloacral dysplasia (MAD) and Restrictive Dermopathy.