Proteins

A protein molecule is made up of a long chain of amino acids each linked to its neighbor through a covalent peptide bond. They are therefore referred to as polypeptides.

Amino Acids

Amino acids are the building blocks of proteins. The structure of amino acids consists of a central carbon atom that is bonded to:

• one carboxylic acid group
• one amino group
• a side group (side-chain)

The side group is responsible for the uniqueness of an amino acid since it affects its:

• shape
• size
• composition
• pH
• charge

Amino Acids

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Folding, Assembly and Post-translational modification of Proteins

During insertion, nascent membrane proteins have to:

• adopt the correct orientation in the lipid bilayer
• undergo covalent modifications
• cleavage of the signal sequence
• N-linked glycosylation
• fold properly
• adopt their native state
• through interaction with ER-resident proteins such as chaperones

It is important to know that many of the proteins present in the lumen of the ER are in transit to other destinations. Others who are residents of the ER carry an "ER retention signal" composed of four amino acids at the C-terminus.

Two ER resident proteins are important:

1. protein disulfide isomerase (PDI) - catalyses the formation of disulfide bonds (S--S) from free sulfhydryl groups (SH) on cysteines
2. binding protein (BiP) - an hsp70-like chaperone that helps in translocation of proteins and also recognizes incorrectly folded proteins

Protein Translocation into ER + Signal Recognition Particle

The Endoplasmic Reticulum membrane is a busy place like an airport. Most of the integral membrane proteins and soluble proteins are co-translationally targeted, inserted and assembled here at sites referred to as translocons which consist of a group of membrane proteins that act in concert with ribosomes and molecular chaperones to facilitate:

• the insertion of integral membrane proteins into the lipid bilayer
• the translocation of soluble proteins into the ER lumen

ER Signal Sequences

Protein targeting to the ER membrane can occur co-translationally or post-translationally depending on the hydrophobicity and location of the signal sequence (SS) which consist of:

• a short sequence of hydrophobic residues
• a charged, positive N-terminal region on one side
• an uncharged, polar C-terminal region on the other side

In the post-translational process, the synthesized proteins are targeted and inserted (or translocated) after translation by the cytosolic ribosomes.

In the co-translational process, targeting of soluble and integral membrane proteins is mediated by the conserved Signal Recognition Particle.

The Endoplasmic Reticulum

The Endoplasmic Reticulum (ER) is a strikingly complex structure within the cell and has three morphologically distinct regions: 

1. Sheets of the nuclear envelope
2. A network of interconnected peripheral ER tubules
3. Peripheral ER sheets

Structure of ER, EMBO reports (2010) 11, 515–521

 All three regions exist within the continuous membrane bilayer and corelate with specialized ER functions. They can be easily detected by flourescence microscopy.