The Rules of Protein Structure

• The function of a protein is determined by its shape.
• The shape of a protein is determined by its primary structure (sequence of amino acids).
• The sequence of amino acids in a protein is determined by the sequence of nucleotides in the gene (DNA) encoding it.

• changes in pH (alters electrostatic interactions between charged amino acids)
• changes in salt concentration (does the same)
• changes in temperature (higher temperatures reduce the strength of hydrogen bonds)
• presence of reducing agents (break S-S bonds between cysteines)

None of these agents breaks peptide bonds, so the primary structure of a protein remains intact when it is denatured.

When a protein is denatured, it loses its function.

• A denatured enzyme ceases to function.
• A denatured antibody no longer can bind its antigen.

Often when a protein has been gently denatured and then is returned to normal physiological conditions of temperature, pH, salt concentration, etc., it spontaneously regains its function (e.g. enzymatic activity or ability to bind its antigen).

• The protein has spontaneously resumed its native three-dimensional shape.
• Its ability to do so is intrinsic; no outside agent was needed to get it to refold properly.

• enzymes that add sugars to certain amino acids [Link], and these may be essential for proper folding;
• proteins, called molecular chaperones, that may enable a newly-synthesized protein to acquire its final shape faster and more reliably than it otherwise would.

Chaperones

• As a polypeptide is being synthesized, it emerges (N-terminal first) from the ribosome and the folding process begins.
• However, the emerging polypeptide finds itself surrounded by the watery cytosol and many other proteins.
• As hydrophobic amino acids appear, they must find other hydrophobic amino acids to associate with. Ideally, these should be their own, but there is the danger that they could associate with nearby proteins instead — leading to aggregation and a failure to form the proper tertiary structure.

To avoid this problem, the cells of all organisms contain molecular chaperones that stabilize newly-formed polypeptides while they fold into their proper structure. The chaperones use the energy of ATP to do this work.

Chaperonins

Some proteins are so complex that a subset of molecular chaperones — called chaperonins — is needed.

Chaperonins are hollow cylinders into which the newly-synthesized protein fits while it folds.

• watery cytosol and
• other proteins outside.

Chaperonins also use ATP as the energy source to drive the folding process.

As mentioned above, high temperatures can denature proteins, and when a cell is exposed to high temperatures, several types of molecular chaperones swing into action. For this reason, these chaperones are also called heat-shock proteins (HSPs).

Not only do molecular chaperones assist in the folding of newly-synthesized proteins, but some of them can also unfold aggregated proteins and then refold the protein properly. Protein aggregation is the cause of disorders such as Alzheimer's disease, Huntington's disease, and prion diseases (e.g., "mad-cow" disease). Perhaps some day ways will be found to treat these diseases by increasing the efficiency of disaggregating chaperones.

Despite the importance of chaperones, the rule still holds: the final shape of a protein is determined by only one thing: the precise sequence of amino acids in the protein.

And the sequence of amino acids in every protein is dictated by the sequence of nucleotides in the gene encoding that protein. So the function of each of the thousands of proteins in an organism is specified by one or more genes.