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Overview

The Ependymin protein has been found in many different living organisms. Human ependymin protein can be found in the PDB under 6JLD. There are a few variations of this protein that have been found that fall into the ependymin family of proteins. These proteins were originally known as fish-specific glycoproteins^[1]. Fish ependymin proteins involve the central nervous system and can include plasticity and memory^[1]. For a long time, these proteins were thought to be specific to fish until the recent discovery of many different ependymin proteins that have been found in mammals^[1]. The ependymin family became much larger after this discovery^[1]. They have more recently been discovered in humans and other animals. The exact function of the Ependymin protein is unknown, however many correlations have been studied regarding the nervous system. The ependymin family became divided into four groups after a genome duplication^[2]. These four groups were decided and grouped by their amino acid sequence: 1) brain-specific sequenced proteins unique to teleost fishes and the first known ependymin protein; 2) non-brain specific proteins found in fishes; 3) a family that is not specific to any tissue and found only in deuterostomes; and 4) a unique family that is widely expressed and is found in protostomes deuterostomes and invertebrates^[2]. This protein has a wide array of functions that are dependent on amino acid formation. This very diverse family of proteins has been widely researched for many years.

Human ependymin protein has been shown to be correlated with a few diseases such as Dupuytren’s disease of the plantar fascia and glaucoma [Yong Wei]. These linkages unfortunately have not given a clear look into the function of this protein [Yong Wei].

Location

Fish ependymin protein is present in the extracellular fluid in the brain of fish with an unknown exact function^[3]. The human ependymin protein, however, has been found as a lysosomal protein^[3]. All ependymin proteins have showed endoplasmic reticulum targeting signals in their amino acid sequences, however, on human ependymin proteins a mannose-6-phosphate tag was located as well^[3]. This mannose-6-phosphate tag resembles a protein that is folded in the endoplasmic reticulum and sent to the Golgi apparatus for further modification in which the M6P tag will send it off to the lysosome^[3]. Lysosomal proteins are fairly well known, and many have known functions, however few lysosomal proteins are classified by their location alone [Yong Wei]. Ependymin proteins are unique in the way that no other known protein seems to have similar amino acid sequences which is why it is so important that the function of this protein should be known^[3].

Structure

Consisting of about 200 amino acids, ependymins are considered a secreted glycoprotein^[1]. Ependymin consists of three disulfide linkages joining together an alpha and beta polypeptide chain [Shashoua]. This protein is very unique and is does not contain any long sequences similar to any known polypeptides. [Shashoua]. However, after a closer look, there are a few short amino acid sequences that contain similarities to tubulin, fibronectin, and laminin [Shashoua]. All human ependymin proteins contain two β-sheets that are stacked on top of each other^[3]. These two sheets have a unique curve to them allowing for a deep hydrophobic region to be present on the molecule^[3]. This β sheet structure that contains a curvature has previously only been found in bacteria [Yong Wei]. This includes two segments, one being strands 1-6 and the next being strands 7-11 [Yong Wei]. The β6 and β7 are at opposite ends and exhibit hydrogen bonding with β1 and β11 respectively [Yong Wei]. The three disulfide linkages located on this molecule join together six cysteine residues^[3]. All ependymin related proteins have been shown to have anywhere from four to six cysteine residues^[3].

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The linkages of these cysteine residues are respectively: Cys42 and Cys172, Cys88 and Cys222, and Cys113 and Cys210 as shown above [Yong Wei]. The two chains of this protein are attached through hydrophilic contact [Yong Wei]. The one cysteine residue that is found only in vertebrates is the Cys88 and Cys222 linkage [Yong Wei]. Human ependymin has been shown to be structurally similar to LolA and LolB proteins [Yong Wei]. These similarities include a deep groove for ligand binding, non-traditional N and C terminus, disulfide linkages throughout the chain, and glycosylated elements [Yong Wei]. The folding of the LolA and LolB proteins has been shown to be similar in ependymins; this is important because this has previously only been associated with bacteria [Yong Wei]. We now have more knowledge about eukaryotes and archaea as well through the discovery of the structure of ependymins [Yong Wei]. This protein is unique in that it has two lipid binding grooves the flat region of the homodimer which can be assumed to aid in membrane binding to give a larger contact surface for use in lipid transport [Yong Wei]. As stated previously, research suggests that human ependymin could potentially be a lysosomal protein in which it can undergo lipid catabolism [Yong Wei]. Research suggests that ependymin is not likely to function as an enzyme or be used structurally but more likely to be considered a transporter or activator protein based on its known qualities [Yong Wei]. The evidence obtained does not give conclusive results as per the function of ependymins, however they remain consistent with previous findings [Yong Wei]. Another unique characteristic of human ependymin protein is that it contains a calcium binding site along with two asparagine residues that are glycosylated^[3]. Fish ependymin related proteins still have an unknown function due to lack of knowledge about the protein, however human ependymin protein is slowly being uncovered and the calcium binding sites indicate that this protein could potentially be a secreted protein^[3]. All of these known facts about ependymin related proteins puts us one step closer to understanding how this protein works.

Research Findings on Fish Ependymins

Research on this protein is very important and can help lead us to a known function of ependymin protein. Looking at the ependymin protein alone does not give clear answers. However, when looking at what happens at a synapse during memory formation, we can gain a bigger picture idea of the role of ependymins. The changes that happen to the fibrous insoluble polymers present in the brain of goldfish give rise to the role of ependymins during memory formation. [Shashoua]. These polymers can be polymerized by the fish ependymin protein in the presence of low calcium in the brain [Shashoua]. These biochemical changes were indicative of synaptic changes as well when studying memory formation. [Shashoua]. This does not give a clear answer on the function of ependymin proteins; however, it gives more insight into a potential function and role in the brain of goldfish during memory formation.

Another research study highlighted the role of ependymins in memory formation also through a study with goldfish. He used similar techniques when observing the ependymin protein, but he looked at the concentration of ependymin protein in the brain. In the goldfish that succeeded in their training, ependymin protein increased by about forty percent when compared to those who had not completed any training [Schmidt]. An unusual finding was that shortly after the fish had finished training the levels of ependymin in their brains had decreased prominently before skyrocketing to almost one hundred and forty percent about 10 hours after training [Schmidt]. A general statement can be made about these findings; during memory formation he had found that ependymin proteins had been used to execute molecular reactions [Schmidt]. The drop in ependymin protein could have been explained by low concentrations of the protein triggering more of the proteins to be made and excreted into the extracellular fluid in the brain [Schmidt].

The findings of fish ependymin proteins suggest that this protein plays a role in memory formation through biochemical changes that occur at the synapse when neurological signals are released. Although there has been no proven function of this protein, we can suggest that this protein plays a role in neurological regeneration as well as neurological plasticity.