Identification and Chromosomal Location of Two Human Genes Encoding Enzymes Potentially Involved in Proteolytic Maturation of Farnesylated Proteins

Freije, José M.P.; Blay, Pilar; Pendás, Alberto M.; Cadiñanos, Juan; Crespo, Piero; López-Otı́n, Carlos

doi:10.1006/geno.1999.5834

Cited by 53 publications

(31 citation statements)

References 30 publications

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“…44,76). After ␤3, a short 3 10 -helix (1; the "linking helix") at the right top of the molecule links the sheet with the "active-site helix" ␣2, which contains the short zinc-binding consensus sequence 60 HEXXH 64 (see below). The helices and the sheet of the NTS contribute through their inner surfaces to an internal hydrophobic core, which traverses the entire protein moiety and glues the structure together.…”

Section: Resultsmentioning

confidence: 99%

“…Ste24p was discovered as an enzyme required for maturation of the mating pheromone a-factor in yeast (9). Its mammalian ortholog, farnesylated protein-converting enzyme 1 (FACE1 also known as Zmpste24), performs a critical cleavage that removes the hydrophobic farnesyl-modified tail of prelamin A (10). Knock-out mice show growth retardation, muscular dystrophy, and premature death; similarly, disruptive mutations in humans have drastic consequences for health and life span (11)(12)(13).…”

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confidence: 99%

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A Novel Family of Soluble Minimal Scaffolds Provides Structural Insight into the Catalytic Domains of Integral Membrane Metallopeptidases

López-Pelegrín

Cerdà-Costa

Martínez-Jiménez

et al. 2013

Journal of Biological Chemistry

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Background: Structural characterization of integral-membrane (IM) metallopeptidases (MPs) faces enormous technical hurdles. Results:We have discovered a novel family of minimal MPs, minigluzincins, and determined the crystal structures of the zymogens of two family members. Conclusion:Minigluzincins are valid models for catalytic domains of M48 and M56 family IMMPs. Significance: They provide a high resolution scaffold for the design of small molecule inhibitors of IMMPs.

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

A Novel Family of Soluble Minimal Scaffolds Provides Structural Insight into the Catalytic Domains of Integral Membrane Metallopeptidases

López-Pelegrín

Cerdà-Costa

Martínez-Jiménez

et al. 2013

Journal of Biological Chemistry

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“…Homologs of STE24 from a number of eukaryotic organisms, including mammals, plants, and parasites, encode enzymes that are functionally similar to Ste24, in that when heterologously expressed in yeast they can mediate AAXing of the a-factor CAAX motif (35,36,39,40,93,100,188,254). Mammalian ZMPSTE24 (for zinc metalloprotease Ste24) is the best-characterized homolog (19).…”

Section: Rce1 and Ste24 Are The Founding Members Of Two Distinct Famimentioning

confidence: 99%

Biogenesis of the Saccharomyces cerevisiae Pheromone a -Factor, from Yeast Mating to Human Disease

Michaelis¹,

Barrowman²

2012

Microbiol Mol Biol Rev

106

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SUMMARY The mating pheromone a -factor secreted by Saccharomyces cerevisiae is a farnesylated and carboxylmethylated peptide and is unusually hydrophobic compared to other extracellular signaling molecules. Mature a -factor is derived from a precursor with a C-terminal CAAX motif that directs a series of posttranslational reactions, including prenylation, endoproteolysis, and carboxylmethylation. Historically, a -factor has served as a valuable model for the discovery and functional analysis of CAAX-processing enzymes. In this review, we discuss the three modules comprising the a -factor biogenesis pathway: (i) the C-terminal CAAX-processing steps carried out by Ram1/Ram2, Ste24 or Rce1, and Ste14; (ii) two sequential N-terminal cleavage steps, mediated by Ste24 and Axl1; and (iii) export by a nonclassical mechanism, mediated by the ATP binding cassette (ABC) transporter Ste6. The small size and hydrophobicity of a -factor present both challenges and advantages for biochemical analysis, as discussed here. The enzymes involved in a -factor biogenesis are conserved from yeasts to mammals. Notably, studies of the zinc metalloprotease Ste24 in S. cerevisiae led to the discovery of its mammalian homolog ZMPSTE24, which cleaves the prenylated C-terminal tail of the nuclear scaffold protein lamin A. Mutations that alter ZMPSTE24 processing of lamin A in humans cause the premature-aging disease progeria and related progeroid disorders. Intriguingly, recent evidence suggests that the entire a -factor pathway, including all three biogenesis modules, may be used to produce a prenylated, secreted signaling molecule involved in germ cell migration in Drosophila . Thus, additional prenylated signaling molecules resembling a -factor, with as-yet-unknown roles in metazoan biology, may await discovery.

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“…Expression of AtFACE-2-Previous studies have shown that FACE-2/Rce1 enzymes from human and mice have widespread expression in adult tissues and are present throughout development (10,12). To investigate the expression pattern of the gene encoding the putative A. thaliana CAAX protease described in this work, we carried out a Northern blot analysis of total RNA from A. thaliana seeds, stems, leaves, flowers, and fruits using the AtFACE-2 full-length cDNA as a probe.…”

Section: Identification and Characterization Of The A Thaliana At-famentioning

confidence: 99%

AtFACE-2, a functional Prenylated Protein Protease from Arabidopsis thaliana Related to Mammalian Ras-converting Enzymes

Cadiñanos

Varela

Mandel

et al. 2003

Journal of Biological Chemistry

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Eukaryotic proteins containing a CAAX (A is aliphatic amino acid) C-terminal tetrapeptide sequence generally undergo a lipid modification, the addition of a prenyl group. Proteins that are modified by prenylation, such as Ras GTPases, can be subsequently modified by a proteolytic event that removes a C-terminal tripeptide (AAX). Two distinct proteases have been identified that are involved in the CAAX proteolytic step, FACE-1/Ste24 and FACE-2/Rce1. These proteases have different enzymatic properties, substrate specificities, and biological functions. However, a proposal has been made that plants lack a FACE-2/Rce1-type protease. Here, we describe the isolation of a cDNA from Arabidopsis thaliana that encodes a 311-aa protein with characteristics that are similar to the FACE-2/Rce1 group of enzymes. Northern blot analysis demonstrates widespread expression of this gene in plant tissues. Heterologous expression of the A. thaliana cDNA in yeast restores CAAX proteolytic activity to yeast lacking native CAAX proteases. The recombinant protein produced in this system displays an in vivo substrate specificity profile distinct from AtSte24 and cleaves a farnesylated CAAX tetrapeptide in vitro. These results provide evidence for the existence of a previously unsuspected plant FACE-2/Rce1 ortholog and support the evolutionary conservation of dual CAAX proteolytic systems in eukaryotes.

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Identification and Chromosomal Location of Two Human Genes Encoding Enzymes Potentially Involved in Proteolytic Maturation of Farnesylated Proteins

Cited by 53 publications

References 30 publications

A Novel Family of Soluble Minimal Scaffolds Provides Structural Insight into the Catalytic Domains of Integral Membrane Metallopeptidases

A Novel Family of Soluble Minimal Scaffolds Provides Structural Insight into the Catalytic Domains of Integral Membrane Metallopeptidases

Biogenesis of the Saccharomyces cerevisiae Pheromone a -Factor, from Yeast Mating to Human Disease

AtFACE-2, a functional Prenylated Protein Protease from Arabidopsis thaliana Related to Mammalian Ras-converting Enzymes

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