- [Instructor] In the last two decades
researchers have discovered that the human proteome
is vastly more complex than the human genome.
Post-translational modification of proteins
increases this functional diversity of the proteome,
which is the entire set of proteins
expressed by a genome at a certain time.
The fact that there are way more proteins
than there are genes demonstrates that single genes
can encode for multiple different proteins,
and the increased complexity of the proteome
as compared to the genome
is facilitated by many different mechanisms,
including post-translational modifications,
which help to regulate localization, activity,
and interactions with other cellular molecules.
These modifications can occur at any time
during the life cycle of a protein.
Many proteins are modified
right after translation is completed,
and these modifications help to mediate
folding into proper confirmation,
increase the stability of the nascent protein,
or help to localize this protein
to distinct cellular compartments, like a shipping label.
Other modifications occur after folding is completed,
and a protein has been localized
to its proper cellular locale.
These modifications serve to alter the biological activity
of the protein, either by activating or inactivating
catalytic activity, for example.
Some other modifications serve as markers
that target a protein for degradation.
And besides chemical modifications,
proteins can be modified via cleavage, or proteolysis.
The key thing to remember is that the proteome is dynamic
and responsive to all sorts of changes in stimuli.
And post-translational modifications
are a common mechanism for regulating
these cellular activities.
Now there are many, many types
of post-translational modifications,
so I'll go over only the most common ones here.
And let's start with methylation.
Methylation involves the transfer
of one carbon methyl group's to amino acid side chains
by methyltransferases using S-adenosylmethionine, or SAM,
as the primary methyl group donor.
This can neutralize a negative amino acid charge
when bound to carboxylic acids,
and leads to increased hydrophobicity of the protein.
A well-known use for methylation
is epigenetic regulation of transcription.
Histone methylation and demethylation
can alter the availability of DNA for transcription.
Another type of protein modification is acetylation,
specifically to nitrogen atoms on a protein.
So N-acetylation, which occurs as a nascent protein
is being translated.
The N-terminal methionine on the growing polypeptide chain
is cleaved by methionine amino peptidase,
and then replaced by an acetyl group donated by acetyl-CoA,
via an enzyme called N-acetyltransferase.
Up to 90% of eukaryotic proteins are acetylated this way,
though the biochemical significance of this modification
remains to be known.
Acetylation also occurs on the lysine residues of histones
via the action of histone acetyltransferases.
And this is also used to alter transcription
in the similar manner to that of methylation.
The acetylation of histone helps to promote transcription
by reducing the chromosomal condensation
around these proteins.
The next post-translational modification
that can occur to proteins is called glycosylation,
and it is one of the most significant types
of post-translational modifications
because it has implications on protein folding,
and confirmation, distribution,
stability, and also activity.
Glycosylation involves the addition
of a diverse array of sugar moieties,
and ranges from simple monosaccharide modifications
of transcription factors, to highly, highly complex
branched polysaccharide modifications
of cell surface receptors.
These carbohydrates can be added to the nitrogen atom
in the side chain of asparagine residues,
those are N-linked, or to the oxygen atom in the side chains
of serine or threonine residues.
These are O-linked.
These types of glycosylation changes,
these types of glycosylation changes form major
structural components of cell surface and secreted proteins.
The next modification, lipidation,
is a post-translational modification ployed
to target proteins to particular membrane-bound organelles
such as the endoplasmic reticulum,
Golgi apparatus, or mitochondria.
It is also used to target proteins to endosomes,
lysosomes, and the plasma membrane.
Two types of lipidation modifications
are GPI anchors, and S-palmitoylation.
C-terminal glycosylphosphatidylinositol, or GPI anchors,
help to tether proteins bound to the plasma membrane
of the cell surface.
These hydrophobic moieties are prepared
in the endoplasmic reticulum where they are added
to nascent proteins and used to localize
cell surface proteins to cholesterol,
or sphingolipid-rich areas in the plasma membrane.
S-palmitoylation involves the addition
of 16 carbon long palmitoyl groups
to dilate side chains of cysteine residues.
This modification adds a long hydrophobic chain
that can be used in a similar manner as a GPI anchor.
It helps to anchor proteins
in the hydrophobic cell membrane.
Next is ubiquitination, which is a protein modification
used to target proteins for degradation.
Ubiquitin is a polypeptide consisting of 76 amino acids
that is attached to lysine residues of target proteins
via the C-terminal glycine of ubiquitin.
Polyubiquinated proteins are recognized
by the 26S proteasome, which is an enzyme
that catalyzes the degradation of the protein
and the recycling of the ubiquitin.
Next up is one of the most common
post-translational modifications that you'll come across,
and that's phosphorylation,
which is a reversible modification
that occurs principally on serine,
threonine, or tyrosine residues,
and is used to regulate proteins that play a role
in a vast array of cellular processes.
Including signal transduction pathways,
the cell cycle, cell growth, and apoptosis.
Protein kinases are the enzymes that help facilitate
the phosphate group transfer,
and phosphorylases help to remove them.
And lastly, enzymes called proteases may remove amino acids
from the amino end of the protein,
or cut the peptide chain in the middle.
A process known as proteolysis.
One example of this is the peptide hormone insulin,
which is cut twice after disulphide bonds are formed
and a pro-peptide is removed from the middle of the chain.
The resulting protein consists of two polypeptide chains
connected by disulphide bonds.
Proteases also play roles in cell signaling,
antigen processing, and apoptosis.