Intrinsically Disordered Protein: Difference between revisions

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Tzviya Zeev-Ben-Mordehai, Eric Martz, Jaime Prilusky, Eran Hodis, Wayne Decatur, Joel L. Sussman, Karl Oberholser, David Canner, Alexander Berchansky, Michal Harel

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 <StructureSection load='1jsu' size='400' side='right' scene='' caption=''>
 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 under proper conditions<ref>For the sake of brevity, 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 under proper conditions<ref>For the sake of brevity, 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-lecexture.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><ref name="tompa2002">PMID: 12368089</ref><ref>Summary of the previous paper (Tompa, 2002): The disorder of intrinsically unstructured proteins (IUP's) is crucial to their functions. They may adopt defined but extended structures when bound to cognate ligands. Their amino acid compositions are less hydrophobic than those of soluble proteins. They lack hydrophobic cores, and hence do not become insoluble when heated. About 40% of eukaryotic proteins have at least one long (>50 residues) disordered region. Roughly 10% of proteins in various genomes have been predicted to be fully disordered. Presently over 100 IUP's have been identified; none are enzymes. Obviously, IUP's are greatly underrepresented in the Protein Data Bank, although there are a few cases of an IUP bound to a folded (intrinsically structured) protein. Here, Tompa suggests five functional categories for intrinsically unstructured proteins and domains: entropic chains (bristles to ensure spacing, springs, flexible spacers/linkers), effectors (inhibitors and disassemblers), scavengers, assemblers, and display sites. (Summary by Eric Martz.)</ref><ref>PMID: 18952168</ref><ref>PMID: 15284216</ref>. Some proteins must be unfolded or disordered in order to perform their functions, and others fold only in complex with target structures<ref name="gunasekaran2003">PMID: 12575995</ref><ref>Summary of the previous paper (Gunasekaran ''et al.'', 2003): Argues that proteins involved in extensive protein-protein interactions can function effectively despite having their structure depend upon such interactions, so that as monomers they are natively disordered. Dispensing with the structural framework (scaffold) needed to maintain a stable fold in the monomer increases efficiency by reducing size. This may account for the large percentage (roughly half) of all proteins that are predicted to be natively disordered. (Summary by Eric Martz.)</ref><ref>PMID: 15738986</ref>. These are termed '''intrinsically disordered protein (IDP), intrinsically unstructured protein (IUP), or natively unfolded protein'''.
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-The cyclin-dependent kinases (CDKs) have a central role in coordinating the eukaryotic cell division cycle. CDKs are controlled through several different processes involving the binding of activating cyclin subunits. Complexes of cyclins with CDKs play a central role in the control of the eukaryotic cell cycle. These complexes are inhibited by other proteins termed in general cyclin-CDK inhibitors (CKIs). One example of CKIs is p27<sup>Kip1</sup>. p27<sup>Kip1</sup> is an IUP and it binds to phosphorylated <scene name='User:Tzviya_Zeev-Ben-Mordehai/Sandbox_1/Complex/2'>cyclin/CDK complex</scene> in <scene name='User:Tzviya_Zeev-Ben-Mordehai/Sandbox_1/Extended/2'>an extended conformation</scene> interacting with both <scene name='User:Tzviya_Zeev-Ben-Mordehai/Sandbox_1/Cyca/2'>cyclin A</scene> and <scene name='User:Tzviya_Zeev-Ben-Mordehai/Sandbox_1/Cdk2/3'>CDK2</scene>. On cyclin A, it binds in a groove formed by conserved cyclin box residues. On CDK2, it binds and rearranges the amino-terminal lobe and also inserts into the catalytic cleft, mimicking ATP. [[http://www.proteopedia.org/wiki/index.php/1jsu]]
+The cyclin-dependent kinases (CDKs) have a central role in coordinating the eukaryotic cell division cycle. CDKs are controlled through several different processes involving the binding of activating cyclin subunits. Complexes of cyclins with CDKs play a central role in the control of the eukaryotic cell cycle. These complexes are inhibited by other proteins termed in general cyclin-CDK inhibitors (CKIs). One example of CKIs is p27<sup>Kip1</sup>. p27<sup>Kip1</sup> is an IUP and it binds to phosphorylated <scene name='User:Tzviya_Zeev-Ben-Mordehai/Sandbox_1/Complex/2'>cyclin/CDK complex</scene> in <scene name='User:Tzviya_Zeev-Ben-Mordehai/Sandbox_1/Extended/2'>an extended conformation</scene> interacting with both <scene name='User:Tzviya_Zeev-Ben-Mordehai/Sandbox_1/Cyca/2'>cyclin A</scene> and <scene name='User:Tzviya_Zeev-Ben-Mordehai/Sandbox_1/Cdk2/3'>CDK2</scene> ([[1jsu]]). On cyclin A, it binds in a groove formed by conserved cyclin box residues. On CDK2, it binds and rearranges the amino-terminal lobe and also inserts into the catalytic cleft, mimicking ATP. [[http://www.proteopedia.org/wiki/index.php/1jsu]]
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