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. [5] [6] 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.
Ceramide transferase protein (or CERT) is responsible for the transfer of ceramide from the endoplasmic reticulum (ER) to the Golgi apparatus. Ceramide plays 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). [7]
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. [6]
CERT is a 68kDa protein [8] that consists of three different parts, each of which with a special role:
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 motif with vesicle-associated membrane protein.
The transport of ceramide by CERT requires ATP. [15] 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. [16]
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. [16]
Protein kinase D (PKD) has been found to phosphorylate the SR motif of CERT. [17] Also, CERT is further phosphorylated by the casein kinase 1 family leading to hyperphosphorylation of the SR motif. [18] On the other hand, the integral membrane protein protein phosphatase 2Cε (PP2Cε), which is located on the endoplasmic reticulum induces dephosphorylation of CERT. [19] Dephosphorylated CERT is in the active form in order to be functional and transfer ceramide from ER to Golgi. [20]
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. [21] 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. [21] Moreover, only the (1R, 3R) isomer of HPA-12 has been found to be an active inhibitor [21] and the length of the chain as well as the two hydroxyl-groups are very important for the inhibitory activity. [22]
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. [6]
Sphingolipids are a class of lipids containing a backbone of sphingoid bases, which are a set of aliphatic amino alcohols that includes sphingosine. They were discovered in brain extracts in the 1870s and were named after the mythological sphinx because of their enigmatic nature. These compounds play important roles in signal transduction and cell recognition. Sphingolipidoses, or disorders of sphingolipid metabolism, have particular impact on neural tissue. A sphingolipid with a terminal hydroxyl group is a ceramide. Other common groups bonded to the terminal oxygen atom include phosphocholine, yielding a sphingomyelin, and various sugar monomers or dimers, yielding cerebrosides and globosides, respectively. Cerebrosides and globosides are collectively known as glycosphingolipids.
Lck is a 56 kDa protein that is found inside specialized cells of the immune system called lymphocytes. The Lck is a member of Src kinase family (SFK) and is important for the activation of T-cell receptor (TCR) signaling in both naive T cells and effector T cells. The role of Lck is less prominent in the activation or in the maintenance of memory CD8 T cells in comparison to CD4 T cells. In addition, the constitutive activity of the mouse Lck homolog varies among memory T cell subsets. It seems that in mice, in the effector memory T cell (TEM) population, more than 50% of Lck is present in a constitutively active conformation, whereas less than 20% of Lck is present as active form in central memory T cells. These differences are due to differential regulation by SH2 domain–containing phosphatase-1 (Shp-1) and C-terminal Src kinase.
Lipid signaling, broadly defined, refers to any biological cell signaling event involving a lipid messenger that binds a protein target, such as a receptor, kinase or phosphatase, which in turn mediate the effects of these lipids on specific cellular responses. Lipid signaling is thought to be qualitatively different from other classical signaling paradigms because lipids can freely diffuse through membranes. One consequence of this is that lipid messengers cannot be stored in vesicles prior to release and so are often biosynthesized "on demand" at their intended site of action. As such, many lipid signaling molecules cannot circulate freely in solution but, rather, exist bound to special carrier proteins in serum.
In molecular biology, CD18 is an integrin beta chain protein that is encoded by the ITGB2 gene in humans. Upon binding with one of a number of alpha chains, CD18 is capable of forming multiple heterodimers, which play significant roles in cellular adhesion and cell surface signaling, as well as important roles in immune responses. CD18 also exists in soluble, ligand binding forms. Deficiencies in CD18 expression can lead to adhesion defects in circulating white blood cells in humans, reducing the immune system's ability to fight off foreign invaders.
Lymphocyte antigen 96, also known as "Myeloid Differentiation factor 2 (MD-2)," is a protein that in humans is encoded by the LY96 gene.
Caveolin-1 is a protein that in humans is encoded by the CAV1 gene.
Discs large homolog 1 (DLG1), also known as synapse-associated protein 97 or SAP97, is a scaffold protein that in humans is encoded by the SAP97 gene.
Sterol regulatory element-binding protein 2 (SREBP-2) also known as sterol regulatory element binding transcription factor 2 (SREBF2) is a protein that in humans is encoded by the SREBF2 gene.
Ras-related protein Rab-11A is a protein that in humans is encoded by the RAB11A gene.
cAMP-dependent protein kinase type II-alpha regulatory subunit is an enzyme that in humans is encoded by the PRKAR2A gene.
In enzymology, a ceramide kinase, also abbreviated as CERK, is an enzyme that catalyzes the chemical reaction:
In enzymology, a Goodpasture-antigen-binding protein kinase is an enzyme that catalyzes the chemical reaction
Cux1 is a homeodomain protein that in humans is encoded by the CUX1 gene.
Syntaxin-6 is a protein that in humans is encoded by the STX6 gene.
Interleukin enhancer-binding factor 2 is a protein that in humans is encoded by the ILF2 gene.
Membrane-associated guanylate kinase, WW and PDZ domain-containing protein 1 is an enzyme that in humans is encoded by the MAGI1 gene.
VAMP-Associated Protein A is a protein that in humans is encoded by the VAPA gene. Together with VAPB and VAPC it forms the VAP protein family. They are integral endoplasmic reticulum membrane proteins of the type II and are ubiquitous among eukaryotes.
Phosphatidylinositol 4-kinase 2-alpha is an enzyme that in humans is encoded by the PI4K2A gene.
Sodium/hydrogen exchanger 6 is an integral membrane protein that in humans is encoded by the SLC9A6 gene. It was originally thought to be a mitochondrial-targeted protein, but subsequent studies have localized it to the plasma membrane and recycling endosomes.
A FFAT motif is a protein sequence motif of six defined amino acids plus neighbouring residues that binds to proteins in the VAP protein family.
