The difference between enzymatically active and inactive homologues has been noted (and in some cases, understood when comparing catalytically active and inactive proteins residing in recognisable families) for some time at the sequence level,
owing to the absence of key catalytic residues. Some pseudoenzymes have also been referred to as 'prozymes' when they were analysed in protozoan parasites.
The best studied pseudoenzymes reside amongst various key signalling superfamilies of enzymes, such as the
modifying enzymes.
and pseudoenzymes are now beginning to be more thoroughly studied in terms of their biology and function, in large part because they are also interesting potential targets (or anti-targets) for drug design in the context of intracellular cellular signalling complexes.
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| Allosteric regulation of conventional protein kinase | STRADα regulates activity of the conventional protein kinase, LKB1
JAK1-3 and TYK2 C-terminal tyrosine kinase domains are regulated by their adjacent pseudokinase domain
KSR1/2 regulates activation of the conventional protein kinase, Raf
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| VRK3 regulates activity of the phosphatase, VHR |
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| Caulobacter DivL binds the phosphorylated response regulator, DivK, allowing DivL to negatively regulate the asymmetric cell division regulatory kinase, CckA |
| Pseudophosphatase
| EGG-4/EGG-5 binds to the phosphorylated activation loop of the kinase, MBK-2
STYX competes with DUSP4 for binding to ERK1/2 |
| Allosteric regulation of conventional phosphatases | MTMR13 binds and promotes lipid phosphatase activity of MTMR2 |
| STYX acts as a nuclear anchor for ERK1/2 |
| STYX binds the F-box protein, FBXW7, to inhibit its recruitment to the SCF Ubiquitin ligase complex |
| cFLIP binds and inhibits the cysteine protease, Caspase-8, to block extrinsic apoptosis |
| Mammalian iRhom proteins bind and regulate trafficking single pass transmembrane proteins to plasma membrane or ER-associated degradation pathway |
| KIAA0157 is crucial to assembly of a higher order heterotetramer with DUB, BRCC36, and DUB activity |
| Mms2 is a ubiquitin E2 variant (UEV) that binds active E2, Ubc13, to direct K63 ubiquitin linkages |
| Tsg101 is a component of the ESCRT-I trafficking complex, and plays a key role in HIV-1 Gag binding and HIV budding |
| BRcat regulates interdomain architecture in RBR family E3 Ubiquitin ligases, such as Parkin and Ariadne-1/2 |
| CPSF-100 is a component of the pre-mRNA 3´ end processing complex containing the active counterpart, CPSF-73 |
| EccC comprises two pseudoATPase domains that regulate the N-terminal conventional ATPase domain |
| GTP-bound Rnd1 or Rnd3/RhoE bind p190RhoGAP to regulate the catalytic activity of the conventional GTPase, RhoA |
| MiD51, which is catalytically dead but binds GDP or ADP, is part of a complex that recruits Drp1 to mediate mitochondrial fission. CENP-M cannot bind GTP or switch conformations, but is essential for nucleating the CENP-I, CENP-H, CENP-K small GTPase complex to regulate kinetochore assembly |
| Yeast light intermediate domain (LIC) is a pseudoGTPase, devoid of nucleotide binding, which binds the dynein motor to cargo. Human LIC binds GDP in preference to GTP, suggesting nucleotide binding could confer stability rather than underlying a switch mechanism. |
| YKL-39 binds, but does not process, chitooligosaccharides via 5 binding subsites |
| Pseudosialidase
| CyRPA nucleates assembly of the P. falciparum PfRh5/PfRipr complex that binds the erythrocyte receptor, basigin, and mediates host cell invasion
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| Pseudolyase
| Prozyme heterodimerisation with S-adenosylmethionine decarboxylase (AdoMetDC) activates catalytic activity 1000-fold
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| Pseudotransferase
| Viral GAT recruits cellular PFAS to deaminate RIG-I and counter host antiviral defence. T. brucei deoxyhypusine synthase (TbDHS) dead paralog, DHSp, binds to and activates DHSc >1000-fold.
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| Pseudo-histone acetyl transferase (pseudoHAT) | Possible scaffold for assembly of signalling complexes| Human O-GlcNAcase (OGA) lacks catalytic residues and acetyl CoA binding, unlike bacterial counterpart
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| Pseudo-phospholipase | Possible scaffold for assembly of signalling complexes| FAM83 family proteins presumed to have acquired new functions in preference to ancestral phospholipase D catalytic activity
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| Viper phospholipase A2 inhibitor structurally resembles the human cellular protein it targets, phospholipase A2. |
| Pseudo-oxidoreductase | Allosteric inactivation of conventional enzyme counterpart| ALDH2*2 thwarts assembly of the active counterpart, ALDH2*1, into a tetramer.
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| Pseudo-dismutase | Allosteric activation of conventional enzyme counterpart| Copper chaperone for superoxide dismutase (CCS) binds and activates catalysis by its enzyme counterpart, SOD1
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| Pseudo-dihydroorotase | Regulating folding or complex assembly of conventional enzyme | Pseudomonas pDHO is required for either folding of the aspartate transcarbamoylase catalytic subunit, or its assembly into an active oligomer |
| Pseudo-RNase | Facilitating complex assembly/stability and promoting association of catalytic paralog | KREPB4 may act as a pseudoenzyme to form the noncatalytic half of an RNase III heterodimer with the editing endonuclease(s) |
