Pseudophosphatases

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Pseudophosphatases are proteins with strong structural and sequence similarity to active phosphatases, but that have sequence changes to the active site that make them catalytically inactive. They are found in all eukaryotes and tend to be deeply conserved [1], suggesting that they continue to have important biological functions.

Pseudophosphatase Overview

CC1 fold

CC1 fold phosphatases have an active site of CxxxxxR, and pseudophosphatases are computationally defined by loss of the C or R, which largely correlates with experimental evidence. Some CC1 phosphatases have dual domains, with one active and one an inactive pseudophosphatase domain. Subfamilies that have pseudophosphatase domains in human include:

• CDC14 subfamily, where CDC14A and CDC14B have dual phosphatase domains, with the first being a pseudophosphatase.
• Several myotubularin subfamilies are consistently inactive, and serve as regulators of active myotubularins. These include the MTMR5 (SBF), MTMR10 and MTMR9 subfamilies, covering 6 human genes.
• The DSP family includes pseudophosphatase subfamilies STYX, STYXL1, and a single member of the DSP3 subfamily, DUSP27.
• The PTEN includes an the obligate pseudophosphatase family Auxilin and Tensin, a subfamily with active and inactive members.
• The PTP family contains several subfamilies of receptor PTPs with dual phosphatase domains. In all cases, the second (D2) domain is believed to be inactive. The Cx5R motif is lost in many (PTPRC, PTPRG, PTPRZ in human), and others have modifications to the conserved knrY domain that make them likely unable to bind phosphotyrosine substrates.

Other folds

(draft)

• TIMM50 from the TIM50 subfamily (HAD/FCP) - predicted to be inactive, but shown experimentally to be a phosphatase
• PFKFB3 from the HP fold (HP1/PFKFB)
• PPIP5K1 and PPIP5K2 from HP fold (HP2/PPIP5K subfamily) - predicted to be active, but shown experimentally to be inactive
• PHLPP1 and PHLPP2 from the PPM fold/family are predicted computationally to be inactive, but shown experimentally to be active.
• PPM fold phosphatases PP2D1 (PP2D1 subfamily) and TAB1 (TAB1 subfamily).

Specifics

Auxilin subfamily

There are two members of auxilin subfamily in human, GAK and DNAJC6. Both GAK and DNAJC6 phosphatase domains have been shown to bind to phospholipids [2, 3]. The phosphatase domains of both are predicted to be inactive due to arginine in catalytic motif Cx5R is replaced by alanine.

HP fold

HP1 family

PFKFB subfamily

PFKFB has two enzymatic domains: 6-phosphofructo-2-kinase domain and fructose-2,6-bisphosphatase domain.

• Human PFKFB3 has low bisphosphatase activity, which is probably due to the R to S substitution at R motif [4, 5].
• Yeast PFK26 is inactive as indicated by the fructose-2,6-bisphosphatase moiety [6], which probably due to H to S substitution at RH motif.
• Yeast YLR345W is predicted to be inactive, since the substitution of H by C at RH motif is observed.

STS subfamily

C. elegans has an expansion in STS subfamily. It has five members, however, none of them has SH3 or UBA domain that are common among STSs. We observed substitutions in three STSs from RH..R..Hx to RC..A..Ds, --..K..Dn, RS..R..Ha, respectively.

Note: old version Pseudophosphatases (obsolete)

References

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