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a-factor + H2O
fragments of a-factor
a-factor mating pheromone + H2O
?
-
-
-
-
?
a-factor-CaaX + H2O
a-factor + aaX
a-factor-CaaX + H2O
a-factor-C + aaX
Abeta 1-40 + H2O
?
-
-
-
-
?
Abz-K-SKTKC(farnesyl)VI(-dinitrophenyl derivative of lysine) + H2O
?
-
-
-
?
Abz-KSKTKC(farnesyl)VIKD + H2O
?
-
-
-
-
?
Abz-SEKKDNYIIKGV-(4-nitro)-Y + H2O
?
-
-
-
-
?
bovine insulin chain A chain + H2O
?
-
-
-
-
?
bovine insulin chain B chain + H2O
?
-
-
-
-
?
CaM53 + H2O
fragments of CaM53
CaM53 is a prenylated C2+-calmodulin from petunia
-
?
DAEFRHDSGYEVHHQK-(Dabcyl)-LVFFAE-(Edans)-DVGSNK + H2O
?
-
-
-
-
?
human insulin + H2O
?
-
-
-
-
?
K-Ras4b + H2O
?
-
-
-
-
?
METP-(639aa)-RSYLLGNSSPRTQSPQNC(farnesyl)-OCH3 + H2O
METP-(639aa)-RSY + LLGNSSPRTQSPQNC(farnesyl)-OCH3
-
-
-
?
N-(Ac)-Cys-(farnesyl)-Ser-Ile-Met + H2O
?
-
the enzyme can process the prelaminA-specific CAAX sequence
-
-
?
prelamin A + H2O
?
the enzyme removes the farnesylated tail of prelamin A
-
-
?
prelamin A + H2O
lamin A
-
cleavage is dependent on processing at the CAAX-box
-
-
?
prelamin A + H2O
lamin A + ?
RACU88402 + H2O
fragments of RACU88402
RACU88402 is a Rac-like GTPase
-
?
trans,trans-farnesyl bromide + H2O
?
-
-
-
-
?
YIIKGVFWDPA(farnesyl)CVIA + H2O
YIIKGVFWDPA(farnesyl)C + Val-Ile-Ala
-
farnesylated 15-mer peptide containing the mature a-factor sequence and the native a-factor CAAX motif
-
?
YIIKGVFWDPA[farnesyl-C]AMQ + H2O
YIIKGVFWDPA[farnesyl-C] + AMQ
-
-
?
YIIKGVFWDPA[farnesyl-C]VIA + H2O
YIIKGVFWDPA[farnesyl-C] + VIA
-
-
?
additional information
?
-
a-factor + H2O
?
-
-
-
?
a-factor + H2O
?
-
the enzyme has CAAX endopeptidase activity towards a-factor substrate
-
-
?
a-factor + H2O
fragments of a-factor
-
-
?
a-factor + H2O
fragments of a-factor
-
complements yeast ste24DELTA mutant
-
?
a-factor + H2O
fragments of a-factor
-
complements yeast ste24DELTA mutant
-
?
a-factor + H2O
fragments of a-factor
-
Ste24 participates in both N- and C-terminal processing steps of a-factor
-
?
a-factor + H2O
fragments of a-factor
-
Ste24 participates in both N- and C-terminal processing steps of a-factor
-
?
a-factor + H2O
fragments of a-factor
-
mating pheromone a-factor
-
?
a-factor + H2O
fragments of a-factor
-
Ste24 participates in both N- and C-terminal processing steps of a-factor
-
?
a-factor + H2O
fragments of a-factor
-
Ste24 participates in both N- and C-terminal processing steps of a-factor
-
?
a-factor + H2O
fragments of a-factor
-
mutant a-factor, containing a A8G point mutation is not cleaved suggesting that Ste24 N-terminal protease activity is highly discriminating
-
?
a-factor + H2O
fragments of a-factor
-
Ste24 is required for the first of the two N-terminal processing steps of mating pheromone a-factor
-
-
?
a-factor-CaaX + H2O
a-factor + aaX
-
removal of the last three amino acids of carboxyl-terminal sequence motif CaaX, enzyme proteolyzes a-factor with A, V, L, I, C or M at the a1 position, V, L, I, C or M at the a2 position or any amino acid at the X position
-
?
a-factor-CaaX + H2O
a-factor + aaX
-
removal of the last three amino acids of carboxyl-terminal sequence motif CaaX, enzyme proteolyzes a-factor with A,V, L, I, C or M at the a1 position, V, L, I, C or M at the a2 position or any amino acid at the X position
-
?
a-factor-CaaX + H2O
a-factor-C + aaX
-
-
-
?
a-factor-CaaX + H2O
a-factor-C + aaX
-
endoproteolytic cleavage of a C-terminal tripeptide of prenylated proteins with a CaaX motif
?
a-factor-CaaX + H2O
a-factor-C + aaX
-
endoproteolytic cleavage of a C-terminal tripeptide of prenylated proteins with a CAAX motif, enzyme may also play a role in amino-terminal proteolytic processing of a-factor
-
?
a-factor-CaaX + H2O
a-factor-C + aaX
-
endoproteolytic cleavage of a C-terminal tripeptide of prenylated proteins with a CaaX motif
-
?
a-factor-CaaX + H2O
a-factor-C + aaX
-
-
-
-
?
prelamin A + H2O
lamin A + ?
-
-
-
?
prelamin A + H2O
lamin A + ?
-
-
-
-
?
prelamin A + H2O
lamin A + ?
-
enzyme cleaves the prenylated and carboxylmethylated 15-amino acid tail from the C-terminus of prelamin A to yield mature lamin. Mutations in the lamin A gene that eliminate the ZMPSTE24 cleavage site lead to the premature aging disease Hutchinson-Gilford Progeria Syndrome
-
?
prelamin A + H2O
lamin A + ?
the C-terminal 41 amino acids of prelamin A contain sufficient context to allow cleavage of the tail by ZMPSTE24. Mutations in amino acids immediately surrounding the cleavage site (between Y646 and L647) interfere with efficient cleavage of the prelamin A tail, e,g R644C, L648A and N650A, in addition to L647R. 9 of the 15 residues within the cleaved tail that lie immediately upstream of the CAAX motif are not critical for ZMPSTE24-mediated cleavage, duplication of the same 9 amino acids impairs the ability of ZMPSTE24 to cleave prelamin A
-
-
?
prelamin A + H2O
lamin A + ?
-
cleavage occurs between the farnesylated cysteine and the A1 position of the CAAX motif, although the prelamin A peptide is predominantly cleaved between A1 and A2
-
-
?
additional information
?
-
the enzyme does not cleave mutant prelamin A (L647R)
-
-
?
additional information
?
-
-
the enzyme does not cleave mutant prelamin A (L647R)
-
-
?
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1,10-phenanthroline
-
Zn2+ chelator
benzyloxycarbonyl-Phe-Ala-2,4,6-trimethylbenzoyloxymethyl ketone
benzyloxycarbonyl-Phe-Lys-2,4,6-trimethylbenzoyloxymethyl ketone
lovastatin
-
abolishes the conversion of prelamin A into lamin A
benzyloxycarbonyl-Phe-Ala-2,4,6-trimethylbenzoyloxymethyl ketone
-
0.25 mM, 21% inhibition, inhibition is not reversible
benzyloxycarbonyl-Phe-Ala-2,4,6-trimethylbenzoyloxymethyl ketone
-
0.25 mM, 41% inhibition, inhibition is not reversible
benzyloxycarbonyl-Phe-Ala-2,4,6-trimethylbenzoyloxymethyl ketone
-
0.25 mM, 22% inhibition, inhibition is not reversible
benzyloxycarbonyl-Phe-Lys-2,4,6-trimethylbenzoyloxymethyl ketone
-
0.25 mM, 76% inhibition, inhibition is not reversible
benzyloxycarbonyl-Phe-Lys-2,4,6-trimethylbenzoyloxymethyl ketone
-
0.25 mM, 68% inhibition, inhibition is not reversible
benzyloxycarbonyl-Phe-Lys-2,4,6-trimethylbenzoyloxymethyl ketone
-
0.25 mM, 76% inhibition, inhibition is not reversible
lopinavir
-
lopinavir
-
HIV protease inhibitors inhibit ZMPSTE24, leading to an accumulation of farnesyl-prelamin A. The inhibition of ZMPSTE24 by HIV protease inhibitors could play a role in the side effects of these drugs
o-phenanthroline
-
-
o-phenanthroline
-
inhibition of recombinant Ste24 CAAX proteolytic activity
tipranavir
-
tipranavir
-
HIV protease inhibitors inhibit ZMPSTE24, leading to an accumulation of farnesyl-prelamin A. The inhibition of ZMPSTE24 by HIV protease inhibitors could play a role in the side effects of these drugs
additional information
HIV protease inhibitors inhibit ZMPSTE24
-
additional information
-
HIV protease inhibitors inhibit ZMPSTE24
-
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H339A
the mutant shows 1.9% of wild type activity
L425P
the mutation is associated with mandibuloacral dysplasia type B and reduced prelamin A cleavage ability (41.9% of wild type activity)
L462R
the mutation is associated with restrictive dermopathy and reduced prelamin A cleavage ability (6.5% of wild type activity)
L647R
-
prelaminaAct mutant, cannot be cleaved by Zmpste24
N265S/L362F
the mutations are associated with Hutchinson-Gilford progeria syndrome and reduced prelamin A cleavage ability
N265S/Y70S
the mutations are associated with mandibuloacral dysplasia type B and reduced prelamin A cleavage ability
P248L/Q41X
the mutations are associated with mandibuloacral dysplasia type B and reduced prelamin A cleavage ability
P248L/W450X
the mutations are associated with mandibuloacral dysplasia type B and reduced prelamin A cleavage ability
T159/L209del
no residual activity
W302X
the mutation is associated with restrictive dermopathy
W340R/L362F
the mutations are associated with mandibuloacral dysplasia type B and reduced prelamin A cleavage ability
W450X
0.3% of wild-type activity
Y399C
the mutation is associated with mandibuloacral dysplasia type B and reduced prelamin A cleavage ability(25.8% of wild type activity)
E298A
-
ability to complement the mating-defective phenotype of ste24-1 is lost
E298D
-
ability to complement the mating-defective phenotype of ste24-1 is lost
H297A
-
ability to complement the mating-defective phenotype of ste24-1 is lost
H335A
0.4% of wild-type activity
H335A
the mutant shows 1.5% of wild type activity
L362F
1.3% of wild-type activity
L362F
the mutation is associated with restrictive dermopathy
L438F
1.0% of wild-type activity
L438F
the mutation is associated with metabolic syndrome and non-alcoholic fatty liver disease and reduced prelamin A cleavage ability (52.7% of wild type activity)
L94P
2.8% of wild-type activity
L94P
the mutation severely impairs enzyme activity
L94P
the mutation with is associated with mandibuloacral dysplasia type B and reduced prelamin A cleavage ability (11.3% of wild type activity)
N265S
4.3% of wild-type activity
N265S
the mutant shows 26.2% of wild type activity
P248L
4.6% of wild-type activity
P248L
the mutant shows 20.5% of wild type activity
W340R
13.7% of wild-type activity
W340R
the mutant shows 41.7% of wild type activity
additional information
-
identification of compound heterozygous frameshifting mutations in exon 1, c.50delA, and exon 5, c.584_585delAT of the ZMPSTE24 gene in two brothers affected with restrictive dermopathy, who died in the neonatal period. Both deletions are frameshifting and are predicted to cause the appearance of premature termination codons
additional information
neonates with restrictive dermopathy have homozygous or compound heterozygous null mutations in the ZMPSTE24 gene
additional information
-
Zmste24-deficient mice, Zmpste24 deficiency elicits a stress signaling pathway that is evidenced by a marked upregulation of p53 target genes, accompanied by a senescence phenotype at the cellular level and accelerated ageing at the organismal level
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Fujimura-Kamada, K.; Nouvet, F.J.; Michaelis, S.
A novel membrane-associated metalloprotease, Ste24p, is required for the first step of NH2-terminal processing of the yeast a-factor precursor
J. Cell Biol.
136
271-285
1997
Saccharomyces cerevisiae
brenda
Tam, A.; Nouvet, F.J.; Fujimura-Kamada, K.; Slunt, H.; Sisodia, S.S.; Michaelis, S.
Dual roles for Ste24p in yeast a-factor maturation: NH2-terminal proteolysis and COOH-terminal CAAX processing
J. Cell Biol.
142
635-649
1998
Saccharomyces cerevisiae, Homo sapiens
brenda
Schmidt, W.K.; Tam, A.; Fujimura-Kamada, K.; Michaelis, S.
Endoplasmic reticulum membrane localization of Rce1p and Ste24p, yeast proteases involved in carboxyl-terminal CAAX protein processing and amino-terminal a-factor cleavage
Proc. Natl. Acad. Sci. USA
95
11175-11180
1998
Saccharomyces cerevisiae
brenda
Schmidt, W.K.; Tam, A.; Michaelis, S.
Reconstitution of the Ste24p-dependent N-terminal proteolytic step in yeast a-factor biogenesis
J. Biol. Chem.
275
6227-6233
2000
Saccharomyces cerevisiae, Homo sapiens
brenda
Tam, A.; Schmidt, W.K.; Michaelis, S.
The multispanning membrane protein Ste24p catalyzes CAAX proteolysis and NH2-terminal processing of the yeast a-factor precursor
J. Biol. Chem.
276
46798-46806
2001
Saccharomyces cerevisiae
brenda
Bracha, K.; Lavy, M.; Yalovsky, S.
The Arabidopsis AtSTE24 is a CAAX protease with broad substrate specificity
J. Biol. Chem.
277
29856-29864
2002
Homo sapiens (O75844), Saccharomyces cerevisiae (P47154), Saccharomyces cerevisiae, Arabidopsis thaliana (Q8RX88)
brenda
Boyartchuk, V.L.; Rine, J.
Roles pf prenyl protein proteases in maturation of Saccharomyces cerevisiae
Genetics
150
95-1001
1998
Saccharomyces cerevisiae
brenda
Leung, G.K.; Schmidt, W.K.; Bergo, M.O.; Gavino, B.; Wong, D.H.; Tam, A.; Ashby, M.N.; Michaelis, S.; Young, S.G.
Biochemical studies of Zmpste24-deficient mice
J. Biol. Chem.
276
29051-29058
2001
Mus musculus (Q80W54), Mus musculus
brenda
Trueblood, C.E.; Boyartchuk, V.L.; Picologlou, E.A.; Rozema, D.; Poulter, C.D.; Rine, J.
The CaaX proteases, Afc1p and Rce1p, have overlapping but distinct substrate specificities
Mol. Cell. Biol.
20
4381-4392
2000
Saccharomyces cerevisiae
brenda
Boyartchuk.V.L.; Ashby, M.N.; Rine, J.
Modulation of Ras and a-factor function by carboxyl-terminal proteolysis
Science
275
1796-1800
1997
Saccharomyces cerevisiae (P47154)
brenda
Pei, J.; Grishin, N.V.
Type II CAAX prenyl endopeptidases belong to a novel superfamily of putative membrane-bound metalloproteases
Trends Biochem. Sci.
26
275-277
2001
Saccharomyces cerevisiae
brenda
Corrigan, D.P.; Kuszczak, D.; Rusinol, A.E.; Thewke, D.P.; Hrycyna, C.A.; Michaelis, S.; Sinensky, M.S.
Prelamin A endoproteolytic processing in vitro by recombinant Zmpste24
Biochem. J.
387
129-138
2005
Homo sapiens
brenda
Moulson, C.L.; Go, G.; Gardner, J.M.; van der Wal, A.C.; Smitt, J.H.; van Hagen, J.M.; Miner, J.H.
Homozygous and compound heterozygous mutations in ZMPSTE24 cause the laminopathy restrictive dermopathy
J. Invest. Dermatol.
125
913-919
2005
Homo sapiens
brenda
Varela, I.; Cadinanos, J.; Pendas, A.M.; Gutierrez-Fernandez, A.; Folgueras, A.R.; Sanchez, L.M.; Zhou, Z.; Rodriguez, F.J.; Stewart, C.L.; Vega, J.A.; Tryggvason, K.; Freije, J.M.; Lopez-Otin, C.
Accelerated ageing in mice deficient in Zmpste24 protease is linked to p53 signalling activation
Nature
437
564-568
2005
Mus musculus
brenda
Porter, S.B.; Hildebrandt, E.R.; Breevoort, S.R.; Mokry, D.Z.; Dore, T.M.; Schmidt, W.K.
Inhibition of the CaaX proteases Rce1p and Ste24p by peptidyl (acyloxy)methyl ketones
Biochim. Biophys. Acta
1773
853-862
2007
Arabidopsis thaliana, Saccharomyces cerevisiae, Homo sapiens
brenda
Coffinier, C.; Hudson, S.E.; Farber, E.A.; Chang, S.Y.; Hrycyna, C.A.; Young, S.G.; Fong, L.G.
HIV protease inhibitors block the zinc metalloproteinase ZMPSTE24 and lead to an accumulation of prelamin A in cells
Proc. Natl. Acad. Sci. USA
104
13432-13437
2007
Mus musculus
brenda
Smigiel, R.; Jakubiak, A.; Esteves-Vieira, V.; Szela, K.; Halon, A.; Jurek, T.; Levy, N.; De Sandre-Giovannoli, A.
Novel frameshifting mutations of the ZMPSTE24 gene in two siblings affected with restrictive dermopathy and review of the mutations described in the literature
Am. J. Med. Genet. A
152A
447-452
2010
Homo sapiens
brenda
Rivas, D.; Li, W.; Akter, R.; Henderson, J.E.; Duque, G.
Accelerated features of age-related bone loss in zmpste24 metalloproteinase-deficient mice
J. Gerontol. A Biol. Sci. Med. Sci.
64
1015-1024
2009
Mus musculus
brenda
Goulbourne, C.N.; Vaux, D.J.
HIV protease inhibitors inhibit FACE1/ZMPSTE24: a mechanism for acquired lipodystrophy in patients on highly active antiretroviral therapy?
Biochem. Soc. Trans.
38
292-296
2010
Homo sapiens (O75844), Homo sapiens
brenda
Ahmad, Z.; Phadke, S.R.; Arch, E.; Glass, J.; Agarwal, A.K.; Garg, A.
Homozygous null mutations in ZMPSTE24 in restrictive dermopathy: evidence of genetic heterogeneity
Clin. Genet.
81
158-164
2012
Homo sapiens (O75844)
brenda
Barrowman, J.; Hamblet, C.; Kane, M.; Michaelis, S.
Requirements for efficient proteolytic cleavage of prelamin A by ZMPSTE24
PLoS ONE
7
e32120
2012
Homo sapiens (O75844), Homo sapiens
brenda
Spear, E.D.; Hsu, E.T.; Nie, L.; Carpenter, E.P.; Hrycyna, C.A.; Michaelis, S.
ZMPSTE24 missense mutations that cause progeroid diseases decrease prelamin A cleavage activity and/or protein stability
Dis. Model. Mech.
11
dmm033670
2018
Homo sapiens (O75844), Homo sapiens
brenda
Hildebrandt, E.R.; Arachea, B.T.; Wiener, M.C.; Schmidt, W.K.
Ste24p mediates proteolysis of both isoprenylated and non-prenylated oligopeptides
J. Biol. Chem.
291
14185-14198
2016
Saccharomyces mikatae
brenda
Clark, K.M.; Jenkins, J.L.; Fedoriw, N.; Dumont, M.E.
Human CaaX protease ZMPSTE24 expressed in yeast Structure and inhibition by HIV protease inhibitors
Protein Sci.
26
242-257
2017
Homo sapiens (O75844), Homo sapiens
brenda