Protein-cysteine N-palmitoyltransferase HHAT-like protein, also known as glycerol uptake/transporter homologue (Gup1), negatively regulates the N-terminal palmitoylation of Sonic hedgehog (Shh) by hedgehog acyltransferase (HHAT) Skn []. Shh is a signalling molecule involved in embryonic patterning and organogenesis, and these lipid modifications serve to regulate its movement to form the proper concentration gradient.
Protein-cysteine N-palmitoyltransferase, also known as hedgehog acyltransferase (HHAT), catalyses the N-terminal palmitoylation of Sonic hedgehog (Shh) [, , ]. Shh is a signaling molecule involved in embryonic patterning and organogenesis, and these lipid modifications serve to regulate its movement to form the proper concentration gradient. Overexpression of Hedgehog family proteins contributes to the aetiology of many cancers, thus HHAT inhibition is considered a target for tumour growth suppression [].HHAT is a multipass transmembrane enzyme with a membrane-bound O-acyltransferase (MBOAT) homology domain [].
Rab23 is a member of the Rab family of small GTPases. In mouse, Rab23 has been shown to function as a negative regulator in the sonic hedgehog (Shh) signaling pathway. Rab23 mediates the activity of Gli2 and Gli3, transcription factors that regulate Shh signaling in the spinal cord, primarily by preventing Gli2 activation in the absence of Shh ligand []. Rab23 also regulates a step in the cytoplasmic signal transduction pathway that mediates the effect of Smoothened (one of two integral membrane proteins that are essential components of the Shh signaling pathway in vertebrates) [, ].In humans, Rab23 is expressed in the retina []. Mice contain an isoform that shares 93% sequence identity with the human Rab23 and an alternative splicing isoform that is specific to the brain. This isoform causes the murine open brain phenotype, indicating it may have a role in the development of the central nervous system [, ]. GTPase activating proteins (GAPs) interact with GTP-bound Rab and accelerate the hydrolysis of GTP to GDP. Guanine nucleotide exchange factors (GEFs) interact with GDP-bound Rabs to promote the formation of the GTP-bound state. Rabs are further regulated by guanine nucleotide dissociation inhibitors (GDIs), which facilitate Rab recycling by masking C-terminal lipid binding and promoting cytosolic localization. Most Rab GTPases contain a lipid modification site at the C terminus, with sequence motifs CC, CXC, or CCX. Lipid binding is essential for membrane attachment, a key feature of most Rab proteins [].
Sufu, encoding the human ortholog of Drosophila suppressor of fused, appears to have a conserved role in the repression of Hedgehog signalling []. It is a repressor of the Gli and Ci transcription factors of the Hedgehog signalling cascade [], and functions by binding these proteins and preventing their translocation to the nucleus. Sufu has been found to be a tumour-suppressor gene that predisposes individuals to medulloblastoma by modulating the SHH signalling pathway []. Homologues of Sufu have been found in bacteria, though their function is not currently known.This entry is specific for the eukaryotic Sufu proteins and does not include any homolgous bacterial sequences.
Sufu, encoding the human ortholog of Drosophila suppressor of fused, appears to have a conserved role in the repression of Hedgehog signalling []. It is a repressor of the Gli and Ci transcription factors of the Hedgehog signalling cascade [], and functions by binding these proteins and preventing their translocation to the nucleus. Sufu has been found to be a tumour-suppressor gene that predisposes individuals to medulloblastoma by modulating the SHH signalling pathway []. Homologues of Sufu have been found in bacteria, though their function is not currently known.This entry represents the eukaryotic suppressor of fused proteins and their bacterial homologues.
Sufu, encoding the human ortholog of Drosophila suppressor of fused, appears to have a conserved role in the repression of Hedgehog signalling []. It is a repressor of the Gli and Ci transcription factors of the Hedgehog signalling cascade [], and functions by binding these proteins and preventing their translocation to the nucleus. Sufu has been found to be a tumour-suppressor gene that predisposes individuals to medulloblastoma by modulating the SHH signalling pathway []. Homologues of Sufu have been found in bacteria, though their function is not currently known.This entry represents a set of bacterial Sufu homologues which are predicted to function as transcriptional regulators.
Sufu, encoding the human ortholog of Drosophila suppressor of fused, appears to have a conserved role in the repression of Hedgehog signalling []. It is a repressor of the Gli and Ci transcription factors of the Hedgehog signalling cascade [], and functions by binding these proteins and preventing their translocation to the nucleus. Sufu has been found to be a tumour-suppressor gene that predisposes individuals to medulloblastoma by modulating the SHH signalling pathway []. Homologues of Sufu have been found in bacteria, though their function is not currently known.Sufu contains at least two distinct domains: a highly conserved carboxy-terminal region required for binding to the amino-terminal ends of the Gli proteins and a unique amino-terminal domain that binds the carboxy-terminal tail of Gli1 []. This entry represents the N-terminal domain of Sufu. Its structure has an unusual fold composed of bifurcated β-sheet with left-handed β-α-β unit.
Sufu, encoding the human ortholog of Drosophila suppressor of fused, appears to have a conserved role in the repression of Hedgehog signalling []. It is a repressor of the Gli and Ci transcription factors of the Hedgehog signalling cascade [], and functions by binding these proteins and preventing their translocation to the nucleus. Sufu has been found to be a tumour-suppressor gene that predisposes individuals to medulloblastoma by modulating the SHH signalling pathway []. Homologues of Sufu have been found in bacteria, though their function is not currently known.This entry represents a domain found in Sufu and its homologues. It is also found in other proteins that are functionally uncharacterised. In eukaryotic Sufu, an additional domain () is found at the C terminus of the protein. This domain binds to the C-terminal domain of the Gli/Ci transcription factors, inhibiting their activity [].This domain is also found in Immunity protein YqcF from B. subtilis, a component of one of 6 LXG toxin-immunity modules. It neutralizes the toxic activity of cognate toxin YqcG [, ].
The Mediator complex is a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. The Mediator complex, having a compact conformation in its free form, is recruited to promoters by direct interactions with regulatory proteins and serves for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors. On recruitment the Mediator complex unfolds to an extended conformation and partially surrounds RNA polymerase II, specifically interacting with the unphosphorylated form of the C-terminal domain (CTD) of RNA polymerase II. The Mediator complex dissociates from the RNA polymerase II holoenzyme and stays at the promoter when transcriptional elongation begins. The Mediator complex is composed of at least 31 subunits: MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED29, MED30, MED31, CCNC, CDK8 and CDC2L6/CDK11. The subunits form at least three structurally distinct submodules. The head and the middle modules interact directly with RNA polymerase II, whereas the elongated tail module interacts with gene-specific regulatory proteins. Mediator containing the CDK8 module is less active than Mediator lacking this module in supporting transcriptional activation.The head module contains: MED6, MED8, MED11, SRB4/MED17, SRB5/MED18, ROX3/MED19, SRB2/MED20 and SRB6/MED22. The middle module contains: MED1, MED4, NUT1/MED5, MED7, CSE2/MED9, NUT2/MED10, SRB7/MED21 and SOH1/MED31. CSE2/MED9 interacts directly with MED4. The tail module contains: MED2, PGD1/MED3, RGR1/MED14, GAL11/MED15 and SIN4/MED16. The CDK8 module contains: MED12, MED13, CCNC and CDK8. Individual preparations of the Mediator complex lacking one or more distinct subunits have been variously termed ARC, CRSP, DRIP, PC2, SMCC and TRAP.Med12 is a component of the evolutionarily conserved Mediator complex []. The Med12 subunit may specifically regulate transcription of targets of the Wnt signaling pathway and SHH signaling pathway. Med12 is a negative regulator of the Gli3-dependent sonic hedgehog signaling pathway via its interaction with Gli3 within the Mediator. A complex is formed between Med12, Med13, CDK8 and CycC which is responsible for suppression of transcription [].
