Systematic analysis of tropomodulin/tropomyosin interactions uncovers fine-tuned binding specificity of intrinsically disordered proteins |
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Authors: | Uversky Vladimir N Shah Samar P Gritsyna Yulia Hitchcock-DeGregori Sarah E Kostyukova Alla S |
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Affiliation: | Department of Biochemistry and Molecular Biology, Institute for Intrinsically Disordered Protein Research, Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN 46202, USA. vuversky@iupui.edu |
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Abstract: | An intriguing regulatory mechanism is the ability of some proteins to recognize their binding partners in an isoform‐specific manner. In this study we undertook a systematic analysis of the specificity of the tropomodulin (Tmod) interaction with tropomyosin (TM) to show that affinities of different Tmod isoforms to TM are isoform‐dependent. Intrinsic disorder predictions, alignment of sequences, and circular dichroism were utilized to establish a structural basis for these isoform‐specific interactions. The affinity of model peptides derived from the N‐terminus of different TM isoforms to protein fragments that correspond to the two TM‐binding sites of different Tmod isoforms were analyzed. Several residues were determined to be responsible for the isoform‐dependent differences in affinity. We suggest that changing a set of residues rather than a single residue is needed to alter the binding affinity of one isoform to mimic the affinity of another isoform. The general intrinsic disorder predictor, PONDR® VLXT, was shown to be a useful tool for analyzing regions involved in isoform‐specific binding and for predicting the residues important for isoform differences in binding. Knowing the residues responsible for isoform‐specific affinity creates a tool suitable for studying the influence of Tmod/TM interactions on sarcomere assembly in muscle cells or actin dynamics in non‐muscle cells. Copyright © 2011 John Wiley & Sons, Ltd. |
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Keywords: | intrinsically disordered proteins protein–protein interactions tropomodulin tropomyosin circular dichroism |
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