Profile produced by amino acids scales on protein sequences. Genomics Systems Biology. An integrated software for population genetics data analysis. Isoelectric point and molecular weight from protein sequence. Fully automated protein structure homology-modeling server. Genomics Evolution biology , Population genetics. Fast sequential Markov coalescent simulation of genomic data. Genomics Evolution biology. Evolution biology , Population genetics. Possible oligosaccharide structures on proteins from masses.
Transcription is the process of making an RNA copy of a gene sequence. This copy, called a messenger RNA mRNA molecule, leaves the cell nucleus and enters the cytoplasm, where it directs the synthesis of the protein, which it encodes. Here is a more complete definition of transcription: Transcription Translation is the process of translating the sequence of a messenger RNA mRNA molecule to a sequence of amino acids during protein synthesis.
The genetic code describes the relationship between the sequence of base pairs in a gene and the corresponding amino acid sequence that it encodes. In the cell cytoplasm, the ribosome reads the sequence of the mRNA in groups of three bases to assemble the protein.
Here is a more complete definition of translation: Translation. Teachers' Domain is a free educational resource produced by WGBH with funding from the NSF, which houses thousands of media resources, support materials, and tools for classroom lessons. One of these resources focuses on the topics of transcription and translation.
This resource is an interactive activity that starts with a general overview of the central dogma of molecular biology, and then goes into more specific details about the processes of transcription and translation.
There are more than different types of PTMs 27 affecting many aspects of protein functions. According to Figure 1 , we can see that some of these major PTMs occur more frequently and have much more been studied. Finally, one can see that phosphorylation on Ser is the most reported PTM type.
All frequencies are shown in log scale. A Clustergram indicating the frequency of each PTM on different amino acids.
B Frequency of major PTMs. C Frequency of each amino acid that was reported as a modified site. Figure 1A shows a clustergram, indicating the division of the PTMs into four clusters as one can see each phosphorylation, and acetylation has been considered as a separate cluster due to their different patterns of modification on the amino acids. On the other hand, ubiquitination, methylation and amidation are the PTMs with many different target residues and have been clustered as a group.
According to the clustergram, amino acids have been divided into five clusters. Amino acid Lys is the most different amino acid based on the PTM pattern. According to Figure 1 , it is observed that phosphorylation, acetylation and ubiquitination are the most frequent PTMs.
Roughly speaking, according to the type of the modifications, these PTMs can be categorized into three main groups. First and second groups are those PTMs that include the addition of chemical and complex groups to the target residue, respectively.
The first group and the second group include glycosylation, prenylation, myristoylation and palmitoylation. Figure 2 shows a graphical timeline for the discovery of these major PTMs. In this timeline, the organisms in which each PTM was discovered for the first time also have been depicted.
In the following subsections, the 10 most studied PTMs, out of these major ones, are described in more detail. Schematic PTM discovery timeline for 10 major PTMs: phosphorylation 28 , methylation 29 , sulfation 30 , acetylation 31 , ubiquitylation 32 , prenylation 33 , myristoylation 34 , SUMOylation 35 , palmitoylation 36 , different types of glycosylation N-glycosylation 37 , O-glycosylation 38 , C-glycosylation 39 and S-glycosylation 40 , phosphoglycosylation 41 and glycosylphosphatidylinositol GPI anchored Protein phosphorylation was first reported in by Phoebus Levene with the discovery of phosphate in the protein vitellin phosvitin This process is an important reversible regulatory mechanism that plays a key role in the activities of many enzymes, membrane channels and many other proteins in prokaryotic and eukaryotic organisms 44 , This PTM includes transferring a phosphate group from adenosine triphosphate to the receptor residues by kinase enzymes Figure 3A.
Conversely, dephosphorylating or removal of a phosphate group is an enzymatic reaction catalyzed by different phosphatases Phosphorylation is the most studied PTM and one of the essential types of PTM, which often happens in cytosol or nucleus on the target proteins This modification can change the function of proteins in a short time via one of the two principal ways: by allostery or by binding to interaction domains Phosphorylation has a vital role in significant cellular processes such as replication, transcription, environmental stress response, cell movement, cell metabolism, apoptosis and immunological responsiveness 12 , 50 , The first acetylation modification in proteins was discovered by V.
Allfrey in in isolated calf thymus nuclei in vitro Acetylation has an essential role in biological processes such as chromatin stability, protein—protein interaction, cell cycle control, cell metabolism, nuclear transport and actin nucleation 56— Ubiquitylation is one of the most important reversible PTMs.
This modification was firstly studied in by Gideon Goldstein This modification is a versatile PTM and can occur on all 20 amino acids Figure 2. However, it occurs on lysine more frequently.
This PTM has a major role in the degradation of intracellular proteins via the ubiquitin Ub —proteasome pathway in all tissues Ubiquitin can occur in mono- or poly-ubiquitination forms on substrate proteins through specific isopeptide bonds by receptors containing ubiquitin-binding domains.
Ubiquitylation is catalyzed by an enzyme complex that contains ubiquitin-activating E1 , ubiquitin-conjugating E2 and ubiquitin ligase E3 enzymes Figure 3C. Ubiquitinated proteins may be acetylated on Lys, or phosphorylated on Ser, Thr or Tyr residues, and lead to dramatically altering the signaling outcome Ubiquitylation modification in substrate proteins can be removed by several specialized families of proteases called deubiquitinases Ubiquitination plays important roles in stem cell preservation and differentiation by regulation of the pluripotency Ubiquitylation has also played a vital role in many various cell activities such as proliferation, regulation of transcription, DNA repair, replication, intracellular trafficking and virus budding, the control of signal transduction, degradation of the protein, innate immune signaling, autophagy and apoptosis 12 , 66 , Dysfunction in the ubiquitin pathway can lead to diverse diseases such as different cancers, metabolic syndromes, inflammatory disorders, type 2 diabetes and neurodegenerative diseases 68— Research on methylation dates back to Nonetheless, just recently, with the identification of new methyltransferases such as protein arginine methyltransferases PRMTs , and histone lysine methyltransferases HKMTs , has attracted more and more attention Methylation is a reversible PTM, which often occurs in the cell nucleus and on the nuclear proteins such as histone proteins 1 , However, lysine and arginine are the two main target residues in methylation, at least in eukaryotic cells 73 , One of the most biologically important roles of methylation is in histone modification.
Histone proteins, after synthesis of their polypeptide chains, are methylated at Lys, Arg, His, Ala or Asn residues In eukaryotes, methylated arginine has been observed in histone and non-histone proteins Recent studies have shown that methylation is associated with fine tuning of various biological processes ranging from transcriptional regulation to epigenetic silencing via heterochromatin assembly Defect in this modification can lead to various diseases such as cancer, mental retardation Angelman syndrome , diabetes mellitus, lipofuscinosis and occlusive disease 12 , 78 , One of the most complex PTMs in the cell is glycosylation, which is a reversible enzyme-directed reaction Glycosylation occurs in multiple subcellular locations, such as endoplasmic reticulum, the Golgi apparatus, cytosol and the sarcolemma membrane In this modification, oligosaccharide chains are linked to specific residues by covalent bond see Figures 3E and F.
According to the target residues, glycosylation can be classified into six groups: N-glycosylation, O-glycosylation, C-glycosylation, S-glycosylation, phosphoglycosylation and glypiation GPI-anchored 5 , N-glycosylation and O-glycosylation are two major types of glycosylation and have important roles in the maintenance of protein conformation and activity Glycosylation has a great role in many important biological processes such as cell adhesion, cell—cell and cell—matrix interactions, molecular trafficking, receptor activation, protein solubility effects, protein folding and signal transduction, protein degradation, and protein intracellular trafficking and secretion 9— SUMOylation takes place via SUMO 83 that has a three-dimensional structure similar to ubiquitin protein and has been discovered in a wide range of eukaryotic organisms SUMOylation can occur in both cytoplasm and nucleus on lysine residues SUMO family has three isoforms in mammals, four isoforms in humans, two isoforms in yeasts and eight isoforms in plants 1.
In this reaction, SUMO is connected to a lysine residue in substrate protein by covalent linkage via three enzymes, namely activating E1 , conjugating E2 and ligase E3. SUMOylation plays a major role in many basic cellular processes like transcription control, chromatin organization, accumulation of macromolecules in cells, regulation of gene expression and signal transduction 89 , It is also necessary for the conservation of genome integrity An important class of PTMs, called lipidation, includes covalent attachment of lipids to proteins.
The first report of the covalent modification of proteins with lipids dates back to These PTMs are taken place via a great variety of lipids like octanoic acid, myristic acid, palmitic acid, palmitoleic acid, stearic acid, cholesterol, etc. Myristoylation, palmitoylation and prenylation can be considered as the three main types of these lipid modifications 95 , Palmitoylation is described in this subsection, and the other two important ones are described in the subsequent subsections.
Bartels Palmitoylation is the covalent attachment of fatty acids, like palmitic acid on the Cys, Gly, Ser, Thr and Lys 6. S-palmitoylation contains a reversible covalent addition of a carbon fatty acid chains, palmitate, to a cysteine via a thioester linkage Figure 3H Palmitoyl-CoA as the lipid substrate is attached to the target protein by a PAT and removed via acyl protein thioesterases Mostly, S-palmitoylation occurs in eukaryotic cells and plays critical roles in many different biological processes including protein function regulation, protein—protein interaction, membrane—protein associations, neuronal development, signal transduction, apoptosis and mitosis 98— Myristoylation N-myristoylation was discovered by Alastair Aitken in , in bovine brain Although often refers to myristoylation as a PTM, it usually occurs co-translationally This modification is an irreversible PTM that occurs mainly on cytoplasmic eukaryotic proteins.
Myristoylation has been reported in some integral membrane proteins as well Myristoylation happens approximately in 0. In myristoylation after removal of the initiating Met, a carbon saturated fatty acid, called myristic acid, is attached to the N-terminal glycine residue via a covalent bond Figure 3I Myristoylation occurs more frequently on Gly and less frequently on Lys residues 6. Proteins that undergo this PTM play critical roles in regulating the cellular structure and many biological processes such as stabilizing the protein structure maturation, signaling, extracellular communication, metabolism and regulation of the catalytic activity of the enzymes , The first study on prenylation was done in by Yuji KamiIya et al.
It is another important lipid-based PTM, which occurs after translation as an irreversible covalent linkage mainly in the cytosol This reaction occurs on cysteine and near the carboxyl-terminal end of the substrate protein Prenylation has two main forms: farnesylation and geranylation These two forms contain the addition of two different types of isoprenoids to cysteine residues: farnesyl pyrophosphate carbon and geranylgeranyl pyrophosphates carbon , respectively.
In prenylated proteins, one can find a consensus motif at the C-terminal; the motif is CAAX where C is cysteine, A is an aliphatic amino acid and X is any amino acid The prenylation is known as a crucial physiological process for facilitating many cellular processes such as protein—protein interactions, endocytosis regulation, cell growth, differentiation, proliferation and protein trafficking — Observations showed that disruption in this modification plays crucial roles in the pathogenesis of cancer , cardiovascular and cerebrovascular disorders, bone diseases, progeria, metabolic diseases and neurodegenerative diseases , Sulfation was first discovered by Bruno Bettelheim in bovine fibrinopeptide bin in Residues Tyr, Cys, and Ser have been identified as target residues for prenylated proteins 6.
Often, the target residue of this PTM is tyrosine, which happens in the trans-Golgi network. N-sulfation or O-sulfation includes the addition of a negatively charged sulfate group by nitrogen or oxygen to an exposed tyrosine residue on the target protein , Currently, PTS is observed mainly in secreted and transmembrane proteins in multicellular eukaryotes and have not yet been observed in nucleic and cytoplasmic proteins TPSTs govern the transfer of an activated sulfate from 3-phospho adenosine 5-phosphosulfate to tyrosine residues within acidic motifs of polypeptides Figure 3K Recently, it has been observed that PTS has vital roles in many biological processes like protein—protein interactions, leukocyte rolling on endothelial cells, visual functions and viral entry into cells PTMs have a vital role in almost all biological processes and fine-tune numerous molecular functions.
Therefore, the footprints of disruption in PTMs can be seen in many diseases. This network contains 97 diseases and biological processes. Involvement of PTMs in diseases and biological processes. D Involvement of PTMs in disease and biological processes. Besides, one can see that cancer is also one of the most affected diseases. Consistently with this observation, the biological processes related to cancer are among the high-degree nodes signaling, DNA repair, control of replication and apoptosis.
Processes related to apoptosis, protein—protein interaction, signaling, cell cycle control, chromatin assembly, organization and stability, DNA repair, protein degradation, protein trafficking and targeting, regulation of gene expression and transcription control are the other high-degree biological processes. Moreover, we can say that ubiquitylation, prenylation, glycosylation, S-palmitoylation and SUMOylation have the most involvement in diseases.
On the other hand, the PTMs with the highest number of interactions with biological processes are phosphorylation, ubiquitylation, methylation, acetylation and SUMOylation. Putting all together, we can conclude that the disruption in the pathways of these five PTMs has a great impact on the normal functioning of the cell and, as the result, on the organisms. Due to the considerable cost and difficulties of experimental methods for identifying PTMs, recently many computational methods have been developed for predicting PTMs Almost all of these methods need a set of experimentally validated PTMs to build a prediction model.
Therefore, the availability of valid public databases of PTMs is the first step toward this end. There are a variety of such public databases that could be utilized easily by the scientific community for developing computational methods 17 , According to the scope and diversity of the covered PTMs, these databanks can be classified into two main groups: general databases and specific databases.
The general databases contain different types of PTMs, regardless of target residue and organisms. These databases provide a broad scope of information for various PTMs.
The current public PTM databases are greatly different in the number of stored modified proteins, the number of modified sites and the number of covered PTM types. Figure 5 shows a bubble chart of main PTM databases according to these three parameters. Abstract Background Bioinformatics tools are of great significance and are used in different spheres of life sciences.
Publication types Research Support, Non-U. Substances Proteins DNA.
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