2007
DOI: 10.1016/j.bbamcr.2007.03.004
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Inhibition of the CaaX proteases Rce1p and Ste24p by peptidyl (acyloxy)methyl ketones

Abstract: The CaaX proteases Rce1p and Ste24p can independently promote a proteolytic step required for the maturation of certain isoprenylated proteins. Although functionally related, Rce1p and Ste24p are unrelated in primary sequence. They have distinct enzymatic properties, which are reflected in part by their distinct inhibitor profiles. Moreover, Rce1p has an undefined catalytic mechanism, whereas Ste24p is an established zinc-dependent metalloprotease. This study demonstrates that both enzymes are inhibited by pep… Show more

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Cited by 36 publications
(76 citation statements)
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“…TPCK has been shown to be a potent in vivo inhibitor of S6K1, PDK1 and other related kinases with a conserved domain (known as AGC kinases), although an in vitro kinase assay showed that S6K1 is not the direct molecular target of TPCK (Ballif et al, 2001;Grammer and Blenis, 1996). TPCK has also been described as inhibiting the endoprotease responsible for cleaving the C-terminal AAX sequence on RAS (Porter et al, 2007). Alternative mechanisms have been proposed including recent work demonstrating that TPCK blocks specific cysteine residues on IkappaB kinase (IKK) and p65/RelA (Ha et al, 2009).…”
Section: Discussionmentioning
confidence: 99%
“…TPCK has been shown to be a potent in vivo inhibitor of S6K1, PDK1 and other related kinases with a conserved domain (known as AGC kinases), although an in vitro kinase assay showed that S6K1 is not the direct molecular target of TPCK (Ballif et al, 2001;Grammer and Blenis, 1996). TPCK has also been described as inhibiting the endoprotease responsible for cleaving the C-terminal AAX sequence on RAS (Porter et al, 2007). Alternative mechanisms have been proposed including recent work demonstrating that TPCK blocks specific cysteine residues on IkappaB kinase (IKK) and p65/RelA (Ha et al, 2009).…”
Section: Discussionmentioning
confidence: 99%
“…Other reports have suggested that Rce1 may be a noncanonical zinc metalloprotease (202). Several residues important for activity have been identified by mutational analysis but do not provide further clarification of the protease category to which Rce1 belongs (204), nor do standard protease inhibitor studies (206). Until Rce1 can be purified, it will not be possible to know whether it is solely responsible for endoproteolysis or instead whether it requires a binding partner or stimulates another protease.…”
Section: Rce1 and Ste24 Are The Founding Members Of Two Distinct Famimentioning
confidence: 99%
“…Purified Ste24 has been demonstrated to be a zinc metalloprotease (255), as discussed in detail below. Rce1, on the other hand, has been refractory to purification and lacks a recognizable protease motif (33,199,204,206). Thus, it remains possible that Rce1 may be necessary, but not sufficient, for AAXing, functioning to activate an as-yet-unidentified protease.…”
Section: Rce1 and Ste24 Are The Founding Members Of Two Distinct Famimentioning
confidence: 99%
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“…To date, the most advanced drug discovery efforts have focused on farnesyltransferase inhibitors (FTIs) (9,53). Inhibitors of the CaaX proteases and ICMT are also being developed (1,11,28,37,39,48). Disrupting CaaX protein modifications has therapeutic application to other diseases as well.…”
mentioning
confidence: 99%