3.6:
Intrinsically Disordered Proteins
Proteins often have rigid secondary and tertiary structures that can be determined experimentally; however, many proteins have flexible structures without a fixed conformation.
These intrinsically disordered proteins, or IDPs, must change shape to perform their functions in an organism.
Disordered sections of proteins contain many hydrophilic amino acids because their amino acid chain must be soluble in the cytoplasm.
IDPs contain few hydrophobic amino acids when its entire chain is flexible; this is because, unlike compact protein structures, these extended structures do not have a protein core where the hydrophobic amino acids can cluster.
Unlike improperly or unfolded proteins, which are usually either refolded or degraded by the cell, IDPs may never fold into a fixed structure, or may only become ordered under specific cellular conditions.
When a structured arrangement of the amino acid chain forms in an IDP, this is called a disorder to order transition. This can be triggered by a covalent modification or an interaction with another molecule that induces a new conformation.
Some IDPs have small flexible segments connecting rigid sections of protein. The segments tether the globular sections of proteins together while enabling them to either interact or act independently with other targets.
Flexible segments can also act as molecular switches changing the function of a protein depending on its conformation.
IDPs’ flexible shape allows them to interact in unique ways with the surfaces of other proteins. These proteins can wrap around their binding partners or act as molecular glue, bringing various other proteins together.
Because of their flexibility, IDPs can have many different binding partners, and they may take different ordered conformations depending on their interactions. This allows a single protein to play several different roles in the cell.
3.6:
Intrinsically Disordered Proteins
Intrinsically disordered proteins are a group of proteins that do not fold into specific three-dimensional structures. Their structural flexibility allows them to complement ordered proteins to perform functions that are inaccessible to rigid structures. They are more common in eukaryotes than prokaryotes and may either be exclusively intrinsically disordered or hybrid proteins, consisting of a mix of ordered and disordered regions. The absence of a rigid structure in these proteins can be attributed to an abundance of polar and charged amino acid residues and relatively fewer hydrophobic amino acids, promoting an ordered structure.
Several factors influence the shape and level of disorder in a protein, such as pH and temperature. Additionally, other proteins that they bind to or associate with can also influence their shape. This binding can occur through multiple binding sites and can result in the permanent or temporary folding of an intrinsically disordered protein or region. Structural changes are made due to molecular recognition features —short, interaction amenable fragments of disordered proteins that can readily undergo disorder-to-order transitions upon binding to other proteins with defined structures.
Post-translational modifications during or after protein synthesis also contribute to the structure of intrinsically disordered proteins. These could include enzymatic cleavage of a peptide bond in the precursor protein, the formation of disulfide bonds, and covalent modifications of proteins with other molecules or chemical groups.
Suggested Reading
- Uversky, V. N. (2016). Dancing protein clouds: the strange biology and chaotic physics of intrinsically disordered proteins. Journal of Biological Chemistry, 291(13), 6681-6688.