Protein disorder and the evolution of molecular recognition: theory, predictions and observations.
Observations going back more than 20 years show that regions in proteins with disordered backbones can play roles in their binding to other molecules; typically, the disordered regions become ordered upon complex formation. Thought-experiments with Schulz Diagrams, which are defined herein, suggest that disorder-to-order transitions are required for natural selection to operate separately on affinity and specificity. Separation of affinity and specificity may be essential for fine-tuning the molecular interaction networks that comprise the living state. For low affinity, high specificity interactions, our analysis suggests that natural selection would parse the amino acids conferring flexibility in the unbound state from those conferring specificity in the bound state. For high affinity, low specificity or for high affinity, multiple specificity interactions, our analysis suggests that the disorder-to-order transitions enable alternative packing interactions between side chains to accommodate the different binding targets. Disorder-to-order transitions upon binding also have significant kinetic implications as well, by having complex effects on both on- and off-rates. Current data are insufficient to decide on these proposals, but sequence and structure analysis on two examples support further investigations of the role of disorder-to-order transitions upon binding.
Department of Biochemistry & Biophysics, Washington State University, Pullman 99164-4660, USA. dunker@mail.wsu.edu
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Dunker
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Garner
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Guilliot
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Romero
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Albrecht
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Hart
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Obradovic
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Kissinger
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Villafranca
D000465:Algorithms; D000595:Amino Acid Sequence; D001665:Binding Sites; D002147:Calmodulin / Q000737:chemistry; D019143:Evolution, Molecular; D046911:Macromolecular Substances; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D011506:Proteins / Q000737:chemistry* / Q000235:genetics; D012641:Selection, Genetic; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D012984:Software
D002147:Calmodulin; D046911:Macromolecular Substances; D011506:Proteins