For almost 50 years molecular biology was based on two dogmas: (i) equating biological function of the protein with a unique three-dimensional structure and (ii) assuming exquisite specificity in protein complexes. Specificity/selectivity is ensured by unambiguous set of interactions formed between the protein and its ligand (another protein, DNA, RNA or small molecule). Many protein complexes however, contain functionally important/critical regions, which remain highly dynamic in the complex or adopt different conformations.[13] This phenomenon is defined fuzziness. The most pertinent example is the cyclin-dependent kinase inhibitorSic1, which binds to the SCF subunit of Cdc4 in a phosphorylation dependent manner.[14] No regular secondary structures are gained upon phosphorylation and the different phosphorylation sites interchange in the complex.[15]
Classification of fuzzy complexes
Structural ambiguity in protein complexes covers a wide spectrum.[1] In a polymorphic complex, the protein adopts two or more different conformations upon binding to the same partner, and these conformations can be resolved.[16] Clamp,[17] flanking [18][19] and random complexes[20][21] are dynamic, where ambiguous conformations interchange with each other and cannot be resolved. Interactions in fuzzy complexes are usually mediated by short motifs.[22] Flanking regions are tolerant to sequence changes as long as the amino acid composition is maintained, for example in case of linker histone C-terminal domains [23] and H4 histone N-terminal domains.[24]
↑ Wright, Peter E; Dyson, H. Jane (1999). "Intrinsically unstructured proteins: Re-assessing the protein structure-function paradigm". Journal of Molecular Biology. 293 (2): 321–31. doi:10.1006/jmbi.1999.3110. PMID10550212.
↑ Nash, Piers; Tang, Xiaojing; Orlicky, Stephen; Chen, Qinghua; Gertler, Frank B; Mendenhall, Michael D; Sicheri, Frank; Pawson, Tony; Tyers, Mike (2001). "Multisite phosphorylation of a CDK inhibitor sets a threshold for the onset of DNA replication". Nature. 414 (6863): 514–21. Bibcode:2001Natur.414..514N. doi:10.1038/35107009. PMID11734846. S2CID16924667.
↑ Sigalov, Alexander; Aivazian, Dikran; Stern, Lawrence (2004). "Homooligomerization of the Cytoplasmic Domain of the T Cell Receptor ζ Chain and of Other Proteins Containing the Immunoreceptor Tyrosine-Based Activation Motif". Biochemistry. 43 (7): 2049–61. doi:10.1021/bi035900h. PMID14967045.
↑ Fuxreiter, Monika; Simon, Istvan; Bondos, Sarah (2011). "Dynamic protein–DNA recognition: Beyond what can be seen". Trends in Biochemical Sciences. 36 (8): 415–23. doi:10.1016/j.tibs.2011.04.006. hdl:2437/124518. PMID21620710.
↑ Watson, Matthew; Stott, Katherine; Thomas, Jean O (2007). "Mapping Intramolecular Interactions between Domains in HMGB1 using a Tail-truncation Approach". Journal of Molecular Biology. 374 (5): 1286–97. doi:10.1016/j.jmb.2007.09.075. PMID17988686.
↑ Olson, Katie E; Narayanaswami, Pranesh; Vise, Pamela D; Lowry, David F; Wold, Marc S; Daughdrill, Gary W (2005). "Secondary Structure and Dynamics of an Intrinsically Unstructured Linker Domain". Journal of Biomolecular Structure and Dynamics. 23 (2): 113–24. doi:10.1080/07391102.2005.10507052. PMID16060685. S2CID37429006.
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