ctdspl2a

Gene Description

ctdspl2a (CTD small phosphatase-like 2a) is one of two zebrafish co-orthologs of vertebrate CTDSPL2 (SCP4), a nuclear protein phosphatase of the haloacid dehalogenase (HAD) superfamily; its paralog is ctdspl2b. The protein has a disordered N-terminal regulatory region, which in the human protein carries nuclear localization sequences, and a C-terminal FCP1-homology phosphatase domain with the magnesium-dependent DxDx(T/V) catalytic motif. Human and mouse CTDSPL2 dephosphorylate serine and threonine residues on several nuclear substrates, including the RNA polymerase II C-terminal domain (Ser5-preferential), FoxO1/FoxO3a (promoting their nuclear retention and target-gene transcription, including gluconeogenic genes), Smad1/5/8 (attenuating BMP signalling) and mitotic histone H3 Thr3. The zebrafish protein keeps the catalytic motif (DLDET) and a phosphatase domain 97.5% identical to human CTDSPL2. ctdspl2a is maternally supplied and expressed throughout development and in all adult tissues sampled, at two- to three-fold higher levels than ctdspl2b. No functional study of the zebrafish gene has been published.

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0004721 phosphoprotein phosphatase activity	IBA GO_REF:0000033	ACCEPT	Summary: Phosphoprotein phosphatase activity, propagated from the Dullard/SCP family node PTN000258719, whose experimental sources include human CTDSPL2 itself (Q05D32). Reason: The function is ancestral to the family (FCP/SCP, Dullard/CTDNEP1, TIMM50 and plant and yeast homologs are all protein phosphatases), and ctdspl2a keeps every feature needed for it. The catalytic DxDx(T/V) motif is present as DLDET, aligned exactly to human D293-T297, and the FCP1-homology domain is 97.5% identical to human CTDSPL2. Mutating either aspartate of that motif abolishes human SCP4 function. This is the core molecular function of the gene; a more specific child (protein serine/threonine phosphatase activity) is recorded in core_functions. Supporting Evidence: PMID:35021089 SCP4 belongs to the haloacid dehalogenase (HAD) family of proteins, which employ conserved active site aspartates within a DxDx(V/T) motif to remove phosphates from protein or non-protein substrates PMID:35021089 Despite similar expression levels to the wild-type protein, SCP4D293A, SCP4D295A, and SCP4D293A/D295A mutants were unable to support MOLM-13 growth (Figures 3G and 3H). file:DANRE/ctdspl2a/ctdspl2a-bioinformatics/RESULTS.md Both copies keep the DxDx(T/V) catalytic motif (DLDET) and a phosphatase domain at least 96% identical to human CTDSPL2.
GO:0004721 phosphoprotein phosphatase activity	IEA GO_REF:0000117	ACCEPT	Summary: Phosphoprotein phosphatase activity from an ARBA machine-learning rule. Reason: Same assertion as the IBA row, consistent with the conserved catalytic motif and phosphatase domain. Duplicate rows with different evidence are acceptable. Supporting Evidence: file:DANRE/ctdspl2a/ctdspl2a-bioinformatics/RESULTS.md Both copies keep the DxDx(T/V) catalytic motif (DLDET) and a phosphatase domain at least 96% identical to human CTDSPL2.
GO:0005575 cellular_component	ND GO_REF:0000015	ACCEPT	Summary: Root-term ND placeholder for cellular component. Reason: Accurate record that no localization has been determined experimentally for the zebrafish protein. A nucleus location is supplied separately by an IEA row, which this review accepts; the paralog ctdspl2b lacks the ND row only because of how the records were processed. Supporting Evidence: PMID:28506762 SCP4 consists of a regulatory domain (amino acids 1–262), which contains two nuclear locations signaling (NLS), and a catalytic phosphatase domain (amino acids 263–466) that reportedly dephosphorylates Smad1/5
GO:0005634 nucleus	IEA GO_REF:0000117	ACCEPT	Summary: Nucleus from an ARBA rule. Reason: Human and mouse CTDSPL2 are nuclear, chromatin-associated phosphatases, and their N-terminal segment carries importin-binding nuclear localization sequences. Its best-characterized substrates (Pol II CTD, FoxO1/3a, Smad1/5/8, histone H3) are nuclear proteins. The zebrafish N-terminal region is less conserved (52% identical) than the phosphatase domain, so nuclear targeting is an inference, but a well supported one for the family. Supporting Evidence: PMID:26920047 Therefore, SCP4 is a unique chromatin-associated, Ser5-preferential CTD phosphatase that preferentially distributes to transcriptionally silenced gene regions and may participate in gene regulation during erythroid differentiation. PMID:35021089 This result suggests that a function of the SCP4 N-terminal segment is to promote nuclear localization of the full-length protein.
GO:0016791 phosphatase activity	IEA GO_REF:0000002	ACCEPT	Summary: Phosphatase activity from the InterPro Dullard-like phosphatase domain (IPR011948) mapping. Reason: Correct but general; the domain-level mapping cannot say more than phosphatase activity. The protein-level term (phosphoprotein phosphatase activity) is carried by the IBA row, so this IEA adds no error. Supporting Evidence: PMID:26674342 It is well known that CTDSPL2 is a nuclear protein containing FCPH domain and DXDX(T/V) motif.
GO:0045722 positive regulation of gluconeogenesis	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: Positive regulation of gluconeogenesis from an ARBA rule, reflecting the mouse and human finding that SCP4 dephosphorylates FoxO1/3a in hepatocytes. Reason: In mammals SCP4 promotes hepatic gluconeogenesis by dephosphorylating FoxO1/3a and increasing transcription of PEPCK1 and G6PC, and SCP4 knockout mice are hypoglycemic as neonates. That is a direct role (the phosphatase acts on the transcription factors that drive the gluconeogenic genes), not just a requirement. ctdspl2a is expressed in zebrafish liver, but the role has not been examined in fish, and it is one of several physiological roles of the enzyme (FoxO in muscle and cartilage, BMP-Smad, Pol II, mitosis). Kept as a plausible, non-core, homology-based process; the same call is made for ctdspl2b, which is also expressed in liver. Supporting Evidence: PMID:28851713 In this study, we discovered a nuclear phosphatase, SCP4/CTDSPL2 (SCP4), that dephosphorylated FoxO1/3a and promoted FoxO1/3a transcription activity. PMID:28851713 Moreover, we demonstrated that gene ablation of SCP4 led to hypoglycemia in neonatal mice.

Core Functions

Nuclear HAD-family serine/threonine protein phosphatase (CTDSPL2/SCP4 ortholog) with a conserved DxDx(T/V) catalytic motif; by homology it dephosphorylates nuclear substrates such as the RNA polymerase II CTD, FoxO transcription factors and Smad1/5/8. Enzyme activity has not been measured for the zebrafish protein; the catalytic motif and phosphatase domain are shared with ctdspl2b.

Molecular Function:

phosphoprotein phosphatase activity

Cellular Locations:

nucleus

Supporting Evidence:

PMID:26920047
SCP4 exhibited Ser5-preferential CTD phosphatase activity in vitro, while small interfering RNA-mediated SCP4 knockdown in HeLa cells increased phosphorylation levels of Pol II at Ser5 and Ser7, but not at Ser2.
PMID:28506762
Our interest in SCP4 (also called CTDSPL2) was stimulated by the finding that SCP4 specifically dephosphorylates transcription factor Smad1/5/8; these reactions attenuate BMP-induced transcriptional activities [26;27].
PMID:42315649
Here, we identify the nuclear phosphatase SCP4 as a novel H3T3 phosphatase through a systematic phosphatase library screening.
file:DANRE/ctdspl2a/ctdspl2a-bioinformatics/RESULTS.md
Both copies keep the DxDx(T/V) catalytic motif (DLDET) and a phosphatase domain at least 96% identical to human CTDSPL2.

Gene Description

Existing Annotations Review

Core Functions

References

Suggested Questions for Experts

Suggested Experiments

📚 Additional Documentation

Notes

Bioinformatics Results

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