Abstract
BackgroundProteins are involved in many interactions with other proteins leading to networks that regulate and control a wide variety of physiological processes. Some of these proteins, called hub proteins or hubs, bind to many different protein partners. Protein intrinsic disorder, via diversity arising from structural plasticity or flexibility, provide a means for hubs to associate with many partners (Dunker AK, Cortese MS, Romero P, Iakoucheva LM, Uversky VN: Flexible Nets: The roles of intrinsic disorder in protein interaction networks. FEBS J 2005, 272:5129-5148).ResultsHere we present a detailed examination of two divergent examples: 1) p53, which uses different disordered regions to bind to different partners and which also has several individual disordered regions that each bind to multiple partners, and 2) 14-3-3, which is a structured protein that associates with many different intrinsically disordered partners. For both examples, three-dimensional structures of multiple complexes reveal that the flexibility and plasticity of intrinsically disordered protein regions as well as induced-fit changes in the structured regions are both important for binding diversity.ConclusionsThese data support the conjecture that hub proteins often utilize intrinsic disorder to bind to multiple partners and provide detailed information about induced fit in structured regions.
Highlights
Proteins are involved in many interactions with other proteins leading to networks that regulate and control a wide variety of physiological processes
Note that the original induced fit mechanism was defined as changes in a structured binding site upon binding to the partner [28], changes that are analogous to a glove altering its shape to fit a hand. Both theoretical and experimental studies over many years suggested that natively unstructured or intrinsically disordered proteins form multi-structure ensembles that present different structures for binding to different partners [29,30,31,32,33,34,35]. Based on these prior studies, we proposed that molecular recognition via disorder-to-order transitions provides a mechanism for hub proteins to recognize multiple partners [36]
A number of these are downstream targets, such as transcription factors, and others are activators or inhibitors of p53's transactivation function. Many of these interactions have been mapped to regions of the p53 sequence (Figure 1, gray boxes): the N-terminal domain, the C-terminal domain, and the DNA binding domain (DBD)
Summary
Proteins are involved in many interactions with other proteins leading to networks that regulate and control a wide variety of physiological processes. The term ‘hub protein’ is relative to the other proteins in a given PPI network, with no agreed upon number of links separating hubs and non-hubs. Several networks such as the internet, cellular phone systems, social interactions, author citations, and so on, exhibit scale-free architecture. A deleterious mutation of a hub protein is more likely to be lethal [4,5,6,7,8,9] Another advantage is that signals can traverse these networks in a small number of steps, so signal transduction efficiency is improved compared to that expected for random networks [7]
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