PTMs & Functional Regulations

PTMs & Functional Regulations

• More than 300 PTMs are known.

• Permanent PTM includes N-linked glycosylation.

Permanent PTM does not remove easily.
Interaction of sugars with amino acids leads to the folding of the chain.

• Permanent modifications have vital relation with function.

• Transitory modifications have a role with protein conformation.

What is the difference between the structural fold and conformation?

Structural fold ➡️ Global change.

Conformation  ➡️ Local change e.g opening/closing of the active site etc.

Temporary/Transitory Modifications

• It occurs for a certain short period of time.

• It occurs at the same location in an alternative manner.

Two examples can be studied

1. H3 protein (Involved in the formation of chromatin from DNA)
2. Oct 1 (Octamer DNA binding transcription factor).

Example 1:

In nucleosome an octamer of histones is present.

In the compaction of chromatin, H1 is involved. In uncoiling chromatin, first of all, H1 is removed.

Histone deacetylase ➡️ deacetylates the acylated proteins.
DNA has a negative charge and histone proteins are rich in arginine & lysine. Because of being rich in basic amino acids, histones are positively charged. This positive charge stabilizes the negative charge of DNA to form the chromatin structure.
In the case of H3, the tails protruding out have those amino acids available where various modifications can occur. These include:

1. Acetylation (Negative Charge) 
2. Methylation (Steric Hindrance)
3. Phosphorylation (Negative Charge).

N-terminal part of histone remains unfolded & thus protrudes out.
These modifications disturb the folding.

Phosphorylation occurs on Serine & Threonine
Acetylation occurs on Arginine & Lysine.

When acetyltransferase acts then acetyl group is attached & negative charge on protein will increase. The tail will protrude out more & there will be a gap in stabilization with DNA further negatively charged modifications occur histones interaction with each other decrease repulsion increase & ultimately structure will uncondensed.

Serine & threonine are also present among the amino acids in almost the same locations as mentioned above. Here phosphorylation occurs.

Thus packing and unpacking of chromatin involves a combination of these modifications when acetylation increases &methylation decreases with the addition of phosphorylation so there will be un-condensation of chromatin as a negative charge will increase causing repulsion. These modifications are alternating as well.
There are different cases:

Even with phosphate, single monosaccharide residue has alternating modifications.

It complete with phosphate. Sugar attaches to beta anomeric conformation. The hydroxyl groups of sugar become the center of hydrogen bond formation. When sugar is present then the structure will condense. If phosphate is present then the structure will relax.

First H1 removes, then modifications occur on H3.

These are called Epigenetic Controls and play an important role in gene induction.

Lampbrush Chromosome

Actively transcribing regions in chromosomes protruding out make appear like a lampbrush.

Modification	Adding Enzymes	Removing Enzymes
● Acetylation	● Acetyltransferase	● Deactelase
● Methylation	● Methyltransferase	● Demethylase
● Phosphorylation	● Kinase	● Phosphatase
● Glycosylation	● Glycosyltransferase	● Glucosidase

Thus, a dynamic environment is created. Somewhere sugar may have a role in positive regulation and somewhere its role is negative. These modifications bring the chain in conformation complexes break & proteins release i.e associated proteins with DNA in case of unpacking. In the case of packing, there is a reversal of these events i.e proteins associate & complex form.

Example 2:

• Oct 1 is a generalized transcription factor & binds to the promotor of the number of genes.

•  Oct 1 has a domain called DNA Binding Domain which has 2 subdomains.

Some transcription factors bind with DNA directly while some bind with already bound factors. In the case of Oct 1, there is a motif of 8 nucleotides in promotor where it binds i.e octamer. If 2-3 nucleotides change then it can still bind hence it is generalized.

Thus, this Oct 1 can bind to various genes. Helping factors bind as well and with the recruitment of RNA polymerase, the further process occurs. With the variation in the position of Oct 1 different transcription processes initiate.

In some cases, even secondary structure may change a bit due to these modifications. When a modification is in important region e.g a helix is made up of 3.6 amino acids if a change occurs in a turn forming amino acid due to which hydrogen bonds break & structure opens up from there then the secondary structure may also change.

In the side-chain of lysine, there is one amino group on delta carbon.
Arginine has two amino groups one primary & one secondary.
Acetylation occurs on the primary amino group but why it occurs less on arginine no satisfactory answer/reason available.

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