COL4A3BP

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Collagen, type IV, alpha 3 (Goodpasture antigen) binding protein

Rendering based on PDB 2E3M.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
SymbolsCOL4A3BP; CERT; CERTL; GPBP; STARD11
External IDsOMIM: 604677 MGI: 1915268 HomoloGene: 4173 GeneCards: COL4A3BP Gene
EC number2.7.11.1
RNA expression pattern
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez1008768018
EnsemblENSG00000113163ENSMUSG00000021669
UniProtQ9Y5P4Q9EQG9
RefSeq (mRNA)NM_001130105NM_001164222
RefSeq (protein)NP_001123577NP_001157694
Location (UCSC)Chr 5:
74.66 – 74.81 Mb		Chr 13:
96.54 – 96.64 Mb
PubMed search
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Collagen type IV alpha-3-binding protein, also known as ceramide transfer protein (CERT) or StAR-related lipid transfer protein 11 (STARD11) is a protein that in humans is encoded by the COL4A3BP gene.[1][2] The protein contains a pleckstrin homology domain at its amino terminus and a START domain towards the end of the molecule. It is a member of the StarD2 subfamily of START domain proteins.

Function and structure

Ceramide transferase protein (or CERT) is responsible for the transfer of ceramide from the endoplasmic reticulum (ER) to Golgi. Ceramide has a very important role in the metabolism and biosynthesis of sphingolipid. More specifically, it is synthesized at the ER, then is transferred by CERT to Golgi where it is converted to sphingomyelin (SM).[3]

There are two pathways through which this transfer takes place: a major pathway, which is ATP and cytosol-dependent and a minor pathway, which is ATP and cytosol-independent.[2]

CERT is a 68kDa protein[4] that consists of three different parts, each of which has a special role:

  1. Pleckstrin homology domain (PH): It is the aminoterminal domain and it consists of about 100 aminoacid residues.[1][5] The main function of this part of CERT is to recognize and bind various phosphatidyloinositol phosphates (PIPs) with different level of specificity.[6] The isomers of PIPs are distributed to various organelles: PI-4,5-diphosphate goes to the plasma membrane, PI-3-monophosphate to endosomes and PI-4-monophosphate to Golgi.[7] PH domain of wild-type CERT has been found to recognize specifically PI4P and therefore CERT targets the Golgi apparatus or the trans-Golgi network.[8][9][10]
  2. START domain: It consists of about 210 amino acid residues and has an important role in the transfer of ceramide, which is that it can recognize specifically only the natural D-erythro isomer of ceramide and extract it from the membrane.[4]
  3. FFAT motif (two phenylalanines in an acidic tract, that has a conserved sequence "EFFDAxE"): It is a short domain situated between PH and START domain and is the one responsible for the interaction of CERT with ER. More specifically, it binds to the ER resident type II membrane protein, vesicle-associated membrane protein (VAMP) associated protein (VAP), an interaction which is necessary for the transfer of ceramide from the ER to Golgi.[11]

All of these domains are important for the transfer of ceramide, since first of all CERT will extract newly synthesized ceramide from the membrane with the help of its START domain. Then, ceramide will be transferred through the cytosol towards Golgi because of the interaction between the PH domain and PI4P. Finally, interaction with ER is facilitated through the binding of the FFAT domain with Vesicle-associated membrane protein.

Regulation

The transport of ceramide by CERT requires ATP.[12] CERT – when expressed in mammalian cells - has been found to receive a lot of possible phosphorylations at the serine repeat (SR) motif, which is close to the PH domain.[13]

It has been shown that the phosphorylation of this SR motif leads to inactivation of the PI4P-binding and ceramide transferring activities of CERT since it induces an autoinhibitory reaction between the PH and START domains of CERT transforming it from the active form to the inactive form.[13]

Protein kinase D (PKD) has been found to phosphorylate the SR motif of CERT.[14] Also, CERT is further phosphorylated by the CKI family leading to hyperphosphorylation of the SR motif.[15] On the other hand, the integral membrane protein protein phosphatase 2Cε (PP2Cε), which is located on the endoplasmic reticulum induces dephosphorylation of CERT.[16] Dephosphorylated CERT is in the active form in order to be functional and transfer ceramide from ER to Golgi.[17]

Inhibitor HPA-12

The chemically synthesized compound N-(30hydroxy-1-hydroxymethyl-3-phenylpropyl)dodecamide (HPA-12) has been found to be an inhibitor of CERT-mediated ceramide trafficking.[18] More specifically, this drug inhibits the ATP-dependent transport of ceramide from ER to Golgi (and therefore the conversion of ceramide to sphingomyelin), but it does not inhibit protein trafficking. This suggests that Ceramide is still transformed to Glycosylceramide at Golgi. Moreover, it has been shown that it does not inhibit the Sphingomyelin synthase in vitro or in vivo.[18] Moreover, only the (1R, 3R) isomer of HPA-12 has been found to be an active inhibitor[18] and the length of the chain as well as the two hydroxyl-groups are very important for the inhibitory activity.[19]

Clinical significance

This gene encodes a kinase also known as Goodpasture antigen-binding protein that specifically phosphorylates the N-terminal region of the non-collagenous domain of the alpha 3 chain of type IV collagen, known as the Goodpasture antigen. Goodpasture's syndrome is the result of an autoimmune response directed at this antigen. One isoform of this protein is also involved in ceramide intracellular transport. Two transcripts exist for this gene.[2]

References

  1. ↑ 1.0 1.1 Raya A, Revert F, Navarro S, Saus J (Jun 1999). "Characterization of a novel type of serine/threonine kinase that specifically phosphorylates the human goodpasture antigen". J Biol Chem 274 (18): 12642–9. doi:10.1074/jbc.274.18.12642. PMID 10212244. 
  2. ↑ 2.0 2.1 2.2 "Entrez Gene: COL4A3BP collagen, type IV, alpha 3 (Goodpasture antigen) binding protein". 
  3. ↑ Merrill AH (July 2002). "De novo sphingolipid biosynthesis: a necessary, but dangerous, pathway". J. Biol. Chem. 277 (29): 25843–6. doi:10.1074/jbc.R200009200. PMID 12011104. 
  4. ↑ 4.0 4.1 Hanada K, Kumagai K, Yasuda S, Miura Y, Kawano M, Fukasawa M, Nishijima M (December 2003). "Molecular machinery for non-vesicular trafficking of ceramide". Nature 426 (6968): 803–9. doi:10.1038/nature02188. PMID 14685229. 
  5. ↑ Raya A, Revert-Ros F, Martinez-Martinez P, Navarro S, Rosello E, Vieites B, Granero F, Forteza J, Saus J (December 2000). "Goodpasture antigen-binding protein, the kinase that phosphorylates the goodpasture antigen, is an alternatively spliced variant implicated in autoimmune pathogenesis". J. Biol. Chem. 275 (51): 40392–9. doi:10.1074/jbc.M002769200. PMID 11007769. 
  6. ↑ Lemmon MA, Ferguson KM (August 2000). "Signal-dependent membrane targeting by pleckstrin homology (PH) domains". Biochem. J. 350 Pt 1: 1–18. PMC 1221219. PMID 10926821. 
  7. ↑ De Matteis M, Godi A, Corda D (August 2002). "Phosphoinositides and the golgi complex". Current Opinion in Cell Biology 14 (4): 434–47. doi:10.1016/S0955-0674(02)00357-5. PMID 12383794. 
  8. ↑ Hanada K, Kumagai K, Yasuda S, Miura Y, Kawano M, Fukasawa M, Nishijima M (December 2003). "Molecular machinery for non-vesicular trafficking of ceramide". Nature 426 (6968): 803–9. doi:10.1038/nature02188. PMID 14685229. 
  9. ↑ Levine TP, Munro S (April 2002). "Targeting of Golgi-specific pleckstrin homology domains involves both PtdIns 4-kinase-dependent and -independent components". Curr. Biol. 12 (9): 695–704. doi:10.1016/S0960-9822(02)00779-0. PMID 12007412. 
  10. ↑ Wang YJ, Wang J, Sun HQ, Martinez M, Sun YX, Macia E, Kirchhausen T, Albanesi JP, Roth MG, Yin HL (August 2003). "Phosphatidylinositol 4 phosphate regulates targeting of clathrin adaptor AP-1 complexes to the Golgi". Cell 114 (3): 299–310. doi:10.1016/S0092-8674(03)00603-2. PMID 12914695. 
  11. ↑ Loewen CJ, Roy A, Levine TP (May 2003). "A conserved ER targeting motif in three families of lipid binding proteins and in Opi1p binds VAP". EMBO J. 22 (9): 2025–35. doi:10.1093/emboj/cdg201. PMC 156073. PMID 12727870. 
  12. ↑ Funakoshi T, Yasuda S, Fukasawa M, Nishijima M, Hanada K (September 2000). "Reconstitution of ATP- and cytosol-dependent transport of de novo synthesized ceramide to the site of sphingomyelin synthesis in semi-intact cells". J. Biol. Chem. 275 (39): 29938–45. doi:10.1074/jbc.M004470200. PMID 10882735. 
  13. ↑ 13.0 13.1 Kumagai K, Kawano M, Shinkai-Ouchi F, Nishijima M, Hanada K (June 2007). "Interorganelle trafficking of ceramide is regulated by phosphorylation-dependent cooperativity between the PH and START domains of CERT". J. Biol. Chem. 282 (24): 17758–66. doi:10.1074/jbc.M702291200. PMID 17442665. 
  14. ↑ Fugmann T, Hausser A, Schöffler P, Schmid S, Pfizenmaier K, Olayioye MA (July 2007). "Regulation of secretory transport by protein kinase D-mediated phosphorylation of the ceramide transfer protein". J. Cell Biol. 178 (1): 15–22. doi:10.1083/jcb.200612017. PMC 2064413. PMID 17591919. 
  15. ↑ Tomishige N, Kumagai K, Kusuda J, Nishijima M, Hanada K (January 2009). "Casein kinase I{gamma}2 down-regulates trafficking of ceramide in the synthesis of sphingomyelin". Mol. Biol. Cell 20 (1): 348–57. doi:10.1091/mbc.E08-07-0669. PMC 2613112. PMID 19005213. 
  16. ↑ Saito S, Matsui H, Kawano M, Kumagai K, Tomishige N, Hanada K, Echigo S, Tamura S, Kobayashi T (March 2008). "Protein phosphatase 2Cepsilon is an endoplasmic reticulum integral membrane protein that dephosphorylates the ceramide transport protein CERT to enhance its association with organelle membranes". J. Biol. Chem. 283 (10): 6584–93. doi:10.1074/jbc.M707691200. PMID 18165232. 
  17. ↑ Hanada K (2010). "Intracellular trafficking of ceramide by ceramide transfer protein". Proc. Jpn. Acad., Ser. B, Phys. Biol. Sci. 86 (4): 426–37. doi:10.2183/pjab.86.426. PMC 3417804. PMID 20431265. 
  18. ↑ 18.0 18.1 18.2 Kumagai K, Yasuda S, Okemoto K, Nishijima M, Kobayashi S, Hanada K (February 2005). "CERT mediates intermembrane transfer of various molecular species of ceramides". J. Biol. Chem. 280 (8): 6488–95. doi:10.1074/jbc.M409290200. PMID 15596449. 
  19. ↑ Nakamura Y, Matsubara R, Kitagawa H, Kobayashi S, Kumagai K, Yasuda S, Hanada K (August 2003). "Stereoselective synthesis and structure-activity relationship of novel ceramide trafficking inhibitors. (1R,3R)-N-(3-hydroxy-1-hydroxymethyl-3-phenylpropyl)dodecanamide and its analogues". Journal of Medicinal Chemistry 46 (17): 3688–95. doi:10.1021/jm0300779. PMID 12904073. 

Further reading

External links

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