Intrinsically Disordered Protein: Difference between revisions
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It has long been taught that proteins must be properly folded in order to perform their functions. This paradigm derives from work by | It has long been taught that proteins must be properly folded in order to perform their functions. This paradigm derives from work by | ||
Christian B. Anfinsen and coworkers. In the 1960's, they showed that RNAse, when denatured so that 99% of its enzymatic activity was lost, could regain enzymatic activity within seconds when the denaturing agent was removed<ref>This description is oversimplified. RNAse needed to be reduced to break disulfide bonds, as well as using 8 M urea, for denaturation. Oxidation without the denaturant then left an inactive enzyme because the disulfide bonds formed randomly, precluding proper folding except very slowly (many hours). Only when protein disulfide isomerase was added did the re-folding occur at a physiological rate (about a minute). The fact that RNAse could thus be trapped in an inactive conformation under physiological conditions contributed to the insights developed by Anfinsen and his team. Proteins lacking disulfides renatured in seconds. For details, see [http://nobelprize.org/nobel_prizes/chemistry/laureates/1972/anfinsen-lecture.html Anfinsen's Nobel Lecture.</ref>. They concluded that the amino acid sequence is sufficient for a protein to fold into its functional, lowest energy conformation. This work won the [[Nobel_Prizes_for_3D_Molecular_Structure 1972 Nobel Prize]], and was subsequently confirmed and extended by many researchers. | Christian B. Anfinsen and coworkers. In the 1960's, they showed that RNAse, when denatured so that 99% of its enzymatic activity was lost, could regain enzymatic activity within seconds when the denaturing agent was removed<ref>This description is oversimplified. RNAse needed to be reduced to break disulfide bonds, as well as using 8 M urea, for denaturation. Oxidation without the denaturant then left an inactive enzyme because the disulfide bonds formed randomly, precluding proper folding except very slowly (many hours). Only when protein disulfide isomerase was added did the re-folding occur at a physiological rate (about a minute). The fact that RNAse could thus be trapped in an inactive conformation under physiological conditions contributed to the insights developed by Anfinsen and his team. Proteins lacking disulfides renatured in seconds. For details, see [http://nobelprize.org/nobel_prizes/chemistry/laureates/1972/anfinsen-lecture.html Anfinsen's Nobel Lecture.</ref>. They concluded that the amino acid sequence is sufficient for a protein to fold into its functional, lowest energy conformation. This work won the [[Nobel_Prizes_for_3D_Molecular_Structure|1972 Nobel Prize]], and was subsequently confirmed and extended by many researchers. | ||
Recently, it has been recognized that not all proteins function in a folded state<ref>PMID: 10550212</ref><ref>PMID: 11381529</ref><ref>PMID: 11784292</ref>. Some proteins must be unfolded or disordered in order to perform their functions, and others fold only in complex with target structures. These are termed intrinsically disordered proteins (IDP), intrinsically unstructured proteins, or natively unfolded proteins. | Recently, it has been recognized that not all proteins function in a folded state<ref>PMID: 10550212</ref><ref>PMID: 11381529</ref><ref>PMID: 11784292</ref>. Some proteins must be unfolded or disordered in order to perform their functions, and others fold only in complex with target structures. These are termed intrinsically disordered proteins (IDP), intrinsically unstructured proteins, or natively unfolded proteins. | ||
By some estimates, about 10% of all proteins are fully disordered, and about 40% of eukaryotic proteins have at least one long (>50 amino acids) disordered loop. Such sequences, under physiological conditions ''in | By some estimates, about 10% of all proteins are fully disordered, and about 40% of eukaryotic proteins have at least one long (>50 amino acids) disordered loop. Such sequences, under physiological conditions ''in vitro'', display physicochemical characteristics resembling those of random coils. They possess little or no ordered structure, having instead an extended conformation with high intra-molecular flexibility, lacking any tightly packed core. | ||
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