Introduction
Ceratotherium simum
The white rhinoceros (Ceratotherium simum) is considered the largest land mammal after the elephant, it can arrives to measure nearly 2 meters. The white rhinoceros consists of two subspecies: Southern white rhinoceros, with approximately 17.460 wild-living specimens, and Northern white rhinoceros, which has very few remaining.
White rhinos live almost exclusively on Africa's tropical and subtropical grasslands and savannas. They sometimes gather in groups of as many as a dozen individuals. Rhino females reproduce only every two and a half to five years. Their calf does not live on its own until it is about 3 years old. Is interesting to know that they can live up to 40 years.
Approximately Rhino females weigh 1.400–1.700kg while males can weigh more than 3000kg. Paradoxically they are not white, but gray. It have two horns, the foremost more prominent than the other. Thino grow as much as 8 centimeters a year, and have been known to grow up to 1.5 meters long.
Selenoproteins
Selenoproteins are a family of proteins found in both bacteria and eukaryotic genomes that contain a selenocysteine (Sec), an strange aminoacid known as the 21st aminoacid. This rare aminoacid consists in a cysteine which have an atom of selenium instead of sulfur and it is codified by an UGA codon, which is normally a stop codon. Due to this event, specific machinery is needed for the recoding of the UGA codon to Sec and also a concrete DNA sequence located in the 3'-UTR region in eukaryotes and archaea and downstream of Sec-encoding UGA codon in bacteria, the SelenoCysteine Insertion Sequence (SECIS). In bacteria, the process is well-described: SELB is a bifunctional protein consisting of an N-terminal Sec-tRNA-specific EF domain and a C-terminal SECIS RNA-binding domain. Thus, the specific binding will allow the recruitment of the EF to the ribosome as it approaches to the UGA codon. In mammals, a SBP2 is known to be required for Sec incorporation, and together with it the eEFsec protein, as we will see in more details.
However, the maintenance of the selenium and therefore all the required machinery and DNA structure is an evolutionary trade-off between efficacy and the effort of synthesizing it. Thus, some selenocysteines mutate to cysteine keeping most of their functionality, although selenium is described to be more efficient and reactive than sulfur. Therefore, selenoproteins homologs (not containing Sec) have been found both as orthologs and paralogs.
The entire set of selenoproteins found in an organism is known as the selenoproteome. In humans, there are 25 selenoprotein genes, whereas in mouse are found 24 selenoprotein. Along the mammals, up to 28 families are described all together. However, the field is relatively unknown and therefore several selenoproteins are not clearly described nor have an assigned function. Expanding the number of genomes with annotated selenoproteins would help to understand better the function and evolution of selenoproteins.
Biosynthesis
The main feature of selenoproteins is the fact that they contain a selenocysteine (Sec), an aminoacid that is coded by an UGA codon. Usually, this codon will stop the translation, but in some occasions and due to the presence of some cis- and trans- elements in the DNA sequence -typically the SECIS element- together with some machinery proteins -SBP1, SBP2, SecS, eEFsec, Secp43, PSTK-, the UGA codon is identified as a Sec codon, leading to the incorporation of this aminoacid to the protein.
To synthesize the aminoacid selenocysteine a specific tRNA (known as tRNAsec) is needed, because its synthesis will take place directly on this tRNAsec. There are two main features that distinguish tRNAsec from the other tRNAs: they have a 6bp D-stem (usually 3-4bp in other tRNA), probably important in serine phosphorylation, an intermediate step in selenocysteine biosynthesis. Furthermore, the aminoacid receptor arm is longer. Moreover, they contain less modified bases.
The first step in this byosynthesis is the charge of serine on the specific tRNAsec, which will be phosphorylated by PSTK in order to allow the next reaction, meanwhile selenophosphate synthetase 2 will be in charge of preparing the dietary selenium to be incorporated. Eventually, selenocysteine synthase (SecS) will add the phosphorylated selenium to phosphoserine to produce Sec.
Once the sec-tRNAsec is formated, the protein SBP2 will bind to the SECIS element and at the same time will bin eEFsec. This elongation factor will eventually bind the sectRNAsec, thus allowing the whole complex to get closer to the specific region of the UGA codon. All together sets the stage for decoding UGA codon as Sec. Additional cofactors may contribute to this synthesis, such as SECp43, which has been shown to bind tRNAsec, although its function has not been elucidated yet.
Selenoprotein families
DI family
The iodothyronine deiodinases family (DI) is essential in the thyroidal hormones due the role that they have in the activation and deactivation of this hormones. The literature, and also our work, says that we can find 3 of this proteins (DI1, DI2, DI3). This family presents a high level of homology between their members. DI2 is a protein that activates the hormones by deionidation of the outer tyrosol ring. Talking about DI3, the literature says that all of the genes associated to this protein are made by just one exon.
It has been seen that this family is related to the Kashin-Beck disease, and the cause is a selenium or iodine deficiency. As we said before, DIO family is directly related to Thyroid hormone production
Gpx family
Glutathione peroxidases are the largest and best-described selenoprotein family in vertebrates and are expressed in all tissues. In mammals 8 GPx are described (although they are not well-annotated in all species), where 5 (1 to 4 and 6) of them contain a selenocysteine and the other 3 contain a cysteine. Some studies (Toppo S, Vanin S, Bosello V, Tosatto SC (2008) Evolutionary and structural insights into the multifaceted glutathione peroxidase (gpx) superfamily. Antioxid Redox Signal 10: 1501–1514.) suggest that GPx 7 and 8 have evolved from GPx4-like selenoprotein ancestor; while GPx5 and 6 are the most recently evolved from GPx3.
Glutathione peroxidases catalyze a reaction which forms glutathione disulfide from two molecules of reduced glutathione, thus meaning that they act as strong antioxidants. The GPx with Sec are highly conserved.
MsrA
It is a repair enzyme that reduce methionine sulfoxyde residues in cell stress situations. Its role is directly related with delaying the aging process, and the degeneration due oxidative reactions. They are a important point in actual study for their relation with various diseases. Enzymatically his activity is significantly improved when it has the selenoprotein structure (a selenocystein in the active site), and has been used a lot to determinate the importance of selenocystein in redox enzyms.
Sel15
SEL15 is a thioredoxin-like, endoplasmic reticulum-resident protein related with the control of the glycoprotien floding proces. It works through its interaction with Udp-Glucose. Another interesting fact is that SEL15 is related to cancer, it is known that selenuium has a role in cancer prevention due to this position in a genetic locus normaly mutated or delated in cancer. Mutations on this gene affect the interaction with selenium uptake and are related with the etiology of cancer.
SelH
SelH Is one of the ancestral vertebrate selenoprotein which seems to be found in all vertebrate. This protein presents a Trx like fold, with an intranuclear position that can act as a transcription factor due to his capacity to bind to DNA. His function is related to the antioxidant protection against H2O2 by increasing the mitochondrial biogenesis and the CytC production. It also reacts to redox variations facilitating synthesis of genes related to de novo production of GSH, and related with phase II detoxificaction. A up regulation of other selenoprotein in stress situtations is also enhaced by SelH.
SelI
Function not fully understood.
SelK
Is the Selenoprotein analyzed with most pseudogenes and isoforms detected. One fact that could justify is that we have a stop codon in an exon with an splice site, this can increase the translation and produce this variations.
SelM
Sel M is an eukaryotic selenoprotein and is expressed in a variety of tissues, with increased levels in the brain. It is localized to the perinuclear structures, and its N-terminal signal peptide is necessary for protein translocation. It seems to play a role in protecting neurons from oxidative stress.
SelN
SelN is a eukaryotic selenoprotein expressed in skeletal muscle, heart, lung and placenta. It seems to play an important role in congenital myopathy.
SelO
Researchers have found, by using bioinformatics tools, the three-dimensional structure of SelO, which appears to be similar to the protein kinase folding. However, there is no conservation of the His-Arg-Asp motif typically found in kinase. Therefore, they suggest that SelO might have retained catalytic phosphotransferase activity in an atypical active site. Thus, the role of the selenocysteine residue has been largely discussed.
In most eukaryotes and many bacteria, SelO is present as a single-copy protein, while duplicate copies in many metazoans. When talking about SelO there is an interesting phenomenon. Some studies suggested that the common ancestor of Metazoa had a duplicated SelO-like gene, but this duplication is lost in some lineages such as primates, rodents and other mammals lineages. Moreover, the different SelO are not good conserved. Here, we will discuss SelO, and we will suggest the presence of a SelO.2 in C. simum although not much is found in the literature.
SelP
SelP is a secreted protein made up of 2 different domains: the N-terminal domain which contains one selenocysteine while the C-terminal contains the other 9 selenocysteines in H. Sapiens. However, it exhibits variation in the total number of Selenocysteine presents in other mammals, thus suggesting that not all the selenocysteine described are useful for the SelP function. Some isoforms have been described, although not well-characterized. Interestingly, SelP is involved in the general homeostasis of selenium.
SelR
In the literature the SelR family it's seen as only one protein. SelR is a member of the methionine sulfoxide reductase family and works in the process of reduction of the sulfoxymethil group. So it reduces the Methionine-R-Sulfoxide to Methionine. SelR is present in all the animals (except some parasites) and it presence is related to the presence of MsrA. It arrives to be clustered or fused with this gene, and this fact suggests that they can be involved in the same function. In this case we find huge evidences of convergent evolution, because both proteins did not present any homology. We had tried to define the viability of this premise we can compare the position of both. More information will be found in the SELR2 discussion.
SelS
Is a selenoprotein located in the ER membrane that has key function in the retrotranslocation of misfolded proteins of the ER membrane by being a component of the ERAD (Endoplasmic-reticulum-associated protein degradation). It has an important relation with inflammatory diseases due his up regulation related to cytokines. The inflammatory process lead to a release of SelS from the liver. Polymorphisms in the SelS gen or machinery of expression had been described as an increased risk of inflammatory diseases due the plasma increase of inflamatory cytokines, such as TNFalfai IL-1beta. SelS has an anti-apoptotic role and reduces ER stress in peripheral macrophages and brain astrocytes.Finally a polymorphism in the promoter of Sels is directly linked to gastric cancer.
SelU
Mammals contain three Cys-containing SelU proteins (1 to 3). These are supposed to have evolved from fish sequences that contain all selenocysteine, although some studies were not able to find evidence that supports an early Sec to Cys-containing conversion for SelU2 and SelU3 proteins. Thus, in eukaryotic lineages SelU is widely distributed in both forms, Cys or Sec containing. While mammals, land plants, arthropods contain a Cys, fish, birds and echinoderms are Sec-containing.
SelV and SelW
SelVis considered to be arose from a duplication of SelW, and the function of both families remains unknown, although it is known that SelV is expressed only in testes while SelW expression takes place in some organs. Results suggest that evolution SelV by SelW gene duplication might have followed up by the addition of N-terminal sequences. Interestingly, SelV seems to be lost in gorilla, meaning that it might have disappeared in other organisms as well.
SPS family
In humans, there are two isoforms: SPS1 and SPS2. Selenophosphate 1 is a cysteine homologue, whereas selenophosphate synthetase 2 (SPS2) is a selenoprotein which plays a role in the synthesis of the Sec aminoacid. Concretely, it generates the Se donor compound (the selenophosphate) which eventually will be used to form the 21st aminoacid.
SPS2 is found as a selenoprotein in all vertebrates. In mammals, SPS2 gene appeared initially as a multiple exon gene (SPS2a), but then a replacement took place, and it becoms a single exon copy (SPS2b). Both genes have strong SECIS elements.
TR family
TR (thioredoxin reductasa) are involved in the cellular redox maintenance by formation of reduced disulfide bonds. Therefore, what they catalyze is the transformation from the oxidized form of thioredoxin to the reduced one, thus allowing the thioredoxin to regulate the cellular redox situation. In mammals, they are described three TR isozymes: TR1, TR2 and TR3. Analyzing these proteins we find various isoforms.
Sequence-based phylogenetic analyses suggest that mammalian TR1 have evolved from the correspondent protein TR1 in fish by duplication.