5-Prime | Getting Tidy: Protein Folding
What is protein folding? It is the process by which proteins acquire their functional, preordained, three-dimensional structure after they emerge, as linear polymers of amino acids, from the ribosome.
Who discovered it? In the 1940s, Linus Pauling and Robert Corey elucidated the a-helix and the b-sheet, which are considered the two fundamental building blocks of all protein secondary structures. In the early 1970s, Christian Anfinsen showed that a protein's 3-D structure is determined purely by its initial amino acid sequence. Recent research indicates that the folding rate also might be predictable from the sequence. (See Protein Folding: Theory Meets Disease)
When does it occur? Most proteins start folding within a minute, at most, after leaving the ribosome. The completion time varies by orders of magnitude, from less than 1 microsecond to several minutes. Some small proteins can acquire the native state in a single folding event; for large complex proteins, the process can involve many chaperone-assisted intermediate stages. Up to three categories of molecules help in protein folding: chaperones protect the protein during misfolding and rescue the process from kinetic energy traps; folding factors participate in the process, for example, catalyzing bond formation; and folding sensors ensure accuracy of the completed product and trigger appropriate action if dysfunction occurs.
Where does it occur? It all happens in the endoplasmic reticulum (ER). Proteins that misfold are then transported into the cytosol for clearance by processes collectively called ER-associated degradation (ERAD).
What are the steps? Folding involves three to four stages, starting with the primary amino acid chain. The a-helices and b-sheets are both connected and stabilized by the nitrogen-hydrogen bonds and the hydrogen bonds within the carbon monoxide groups.
Most proteins comprise both of these structures, but some are made almost entirely of one; wool, fur, and hair keratins are virtually all a-helix. The tertiary structure is constructed from the looser secondary conformation by a variety of bonding interactions between the side chains of the constituent amino acids. Some of these bonds provide the protein with its physical strength and are stronger than the hydrogen bonds within the secondary structure, covalent disulphide bonds being common.
Quaternary structures are formed through association of multiple native proteins with a variety of bonding interactions, including salt bridges and disulphide bonds providing the strength.