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PTM Descriptions

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Descriptions of different types of post-translational modifications (PTM).

 

Ubiquitin. At roughly 620 members, the ubiquitin ligases represent the largest family of enzymes in human; there are nearly 100 deubiquitylase enzymes that antagonize or reverse the modification. Although best known for its role in protein degradation, ubiquitylation is a highly dynamic and diverse set of modifications with various cellular readouts. Ubiquitin is often singly attached to substrate lysines (monoubiquitylation); but ubiquitin itself has seven lysines- conserved from yeast to human- which can mediate attachment of additional moieties in a sequential fashion (polyubiquitylation, or ubiquitin chains). Thus, this “single” post-translational modification (PTM) is actually a diverse collection of modifications utilizing the same molecule (ubiquitin) in various lengths (1 through very long) and in various arrangements (varying by which lysine joins adjacent moieties). Monoubiquitylation marks sites of DNA damage, or alters protein activity, localization, or interaction. Tetra-ubiquitin chains linked through lysine 48 (K48-chains) are the canonical signal for proteasomal degradation. Chains linked through the amino termini (linear chains) structurally resemble K63 chains, and mediate signaling within the inflammatory response (TNF pathway in particular). K11 chains have been shown to mediate degradation of mitotic checkpoint proteins. The remaining linkages (K6, K27, K29, K33) have all been shown to be present in humans and other eukaryotes in vivo, but definitive roles have not yet been elucidated. For mass spectrometry (MS)-based proteomic study of the ubiquitin pathway, perhaps the greatest limitation is that neither length nor linkage can be assessed following the tryptic digestion necessary to perform the tandem MS; rather, only a residual di-glycine motif at the modified lysine is measured, which is also common to two other non-ubiquitin forms of PTM, namely ISG15ylation and NEDD8ylation.

 

 

Methylation. Protein methylation occurs to Nitrogen and Oxygen (N- and O- linked) of amino acid side chains to increase protein hydrophobicity. It can also mask the negative charge of carboxylic acid side chains. N-Methylation is irreversible, while O-Methylation is potentially reversible. The reversible methylation of histones is one of the best-studied means of epigenetic regulation and affects the accessibility of associated DNA. Like ubiquitylation and glycosylation, this modification contains elements of variable structure, as it is variably found as mono, di-, or tri-methyl groups on proteins.
Methylation is so common within cells that the methyl building block S-adenosyl Methionine (SAM) is second only to ATP in terms of utilization within enzymatic cellular reactions.

 

 

Acetylation. Although 80-90% of eukaryotic proteins are co-translationally acetylated at the N-terminus, the more dynamic and informative version of this modification occurs to the epsilon amine of lysine residues. This is the exact site of ubiquitylation, and these two modifications are known to compete for space on substrate lysines, particularly among proteins that regulate the cell cycle. Histone acetylation and deacetylation is a well-studied mechanism of epigenetic control, but cytoplasmic proteins are acetylated as well. Crosstalk with phosphorylation and methylation is also common.

 

 

Phosphorylation. The roughly 560 kinases represent the second largest family of enzymes in human (behind only the E3 ubiquitin ligases), and are antagonized by nearly 250 human phosphatases. Occurring principally on lysine, serine, and threonine residues, this modification is best known for its role in driving and checking the cell cycle. Ubiquitin-driven degradation of phosphorylated proteins is a particularly important mechanism of cell cycle control. Signaling cascades commonly utilize phosphorylation to control cellular responses, for example within inflammation and apoptotic pathways.

 

 

Glycosylation. The addition of polysaccharide structures to proteins has significant impact to their proper folding, conformation, activity, and stability. Cell surface receptors and secreted proteins often contain extensive and highly branched structures. While glycosylation is common within the endoplasmic reticulum during protein maturation, changes to glyco-structure also occur within the cytoplasm and nucleus in response to various stimuli.

 

 

Our system enables direct, proteome-wide study of the full complexity of modifications from a physiologically relevant starting point. For example, how does an E3 behave alongside 619 other E3’s or the distinct subset thereof within the context of a particular cell at a particular time? How about within the context of ~90 deubiquitylase enzymes – or subsets thereof – editing or reversing its activity? How about while acetylation, methylation, succinylation, biotinylation, ISGylation, SUMOylation, Neddylation, Pupylation, or adenylation machinery is competing for space on substrate lysines? While carbamylation machinery is converting certain lysines to homocitrulline? What happens to activity of the E3 towards substrates as they undergo phosphorylation or any other of the hundreds of post translational modifications known to occur?

 

 

 

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