Caught in self-interaction: Evolutionary and functional mechanisms of protein homooligomerization

National Center for Biotechnology Information, National Library of Medicine, National Institutes ofHealth, Bethesda, MD 20894, USA.
Physical Biology (Impact Factor: 2.54). 06/2011; 8(3):035007. DOI: 10.1088/1478-3975/8/3/035007
Source: PubMed


Many soluble and membrane proteins form homooligomeric complexes in a cell which are responsible for the diversity and specificity of many pathways, may mediate and regulate gene expression, activity of enzymes, ion channels, receptors, and cell adhesion processes. The evolutionary and physical mechanisms of oligomerization are very diverse and its general principles have not yet been formulated. Homooligomeric states may be conserved within certain protein subfamilies and might be important in providing specificity to certain substrates while minimizing interactions with other unwanted partners. Moreover, recent studies have led to a greater awareness that transitions between different oligomeric states may regulate protein activity and provide the switch between different pathways. In this paper we summarize the biological importance of homooligomeric assemblies, physico-chemical properties of their interfaces, experimental and computational methods for their identification and prediction. We particularly focus on homooligomer evolution and describe the mechanisms to develop new specificities through the formation of different homooligomeric complexes. Finally, we discuss the possible role of oligomeric transitions in the regulation of protein activity and compile a set of experimental examples with such regulatory mechanisms.

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Available from: Anna R Panchenko
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    • "Many cellular control mechanisms operate at the level of protein–protein interactions, and main signaling pathways involve dense networks of protein–protein interactions and phosphorylation events. Phosphorylation may not only trigger the transitions between different conformation states of one protein but in some cases may modulate transitions between different conformations or oligomeric states in homooligomeric and heterooligomeric complexes and might represent an important mechanism for regulation of protein activity (Randez-Gil et al., 1998; Jia-Lin Ma and Stern, 2008; Hashimoto et al., 2011). Recently Nishi et al. performed a comprehensive analysis of phosphorylation sites on protein–protein binding interfaces (Nishi et al., 2011). "
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    ABSTRACT: Phosphorylation offers a dynamic way to regulate protein activity and subcellular localization, which is achieved through its reversibility and fast kinetics. Adding or removing a dianionic phosphate group somewhere on a protein often changes the protein's structural properties, its stability and dynamics. Moreover, the majority of signaling pathways involve an extensive set of protein-protein interactions, and phosphorylation can be used to regulate and modulate protein-protein binding. Losses of phosphorylation sites, as a result of disease mutations, might disrupt protein binding and deregulate signal transduction. In this paper we focus on the effects of phosphorylation on protein stability, dynamics, and binding. We describe several physico-chemical mechanisms of protein regulation through phosphorylation and pay particular attention to phosphorylation in protein complexes and phosphorylation in the context of disorder-order and order-disorder transitions. Finally we assess the role of multiple phosphorylation sites in a protein molecule, their possible cooperativity and function.
    Full-text · Article · Aug 2014 · Frontiers in Genetics
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    • "Sirt1 was suggested to form trimers [12], while Sirtuin catalytic domains are mainly monomeric (see the Discussion section), and protein oligomerization often contributes to regulation [37]. To analyse a potential regulatory function of trimer formation and the role of the N- and C-terminal extensions in Sirt1 oligomerization and regulation, we recombinantly produced full-length protein and deletion variants of human Sirt1 (Figure 1A). "
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    ABSTRACT: Sirtuins are NAD+-dependent protein deacetylases regulating metabolism, stress responses, and aging processes. Among the seven mammalian Sirtuins, Sirt1 is the physiologically best-studied isoform. It regulates nuclear functions such as chromatin remodeling and gene transcription, and it appears to mediate beneficial effects of a low calorie diet, which can partly be mimicked by the Sirt1 activating polyphenol resveratrol. The molecular details of Sirt1 domain architecture and regulation, however, are little understood. It has unique N- and C-terminal domains flanking a conserved Sirtuin catalytic core, and these extensions are assumed to mediate Sirt1-specific features such as homo-oligomerization and activation by resveratrol. To analyze the architecture of human Sirt1 and functions of its N- and C-terminal extensions, we recombinantly produced Sirt1 and Sirt1 deletion constructs as well as the "active regulator of Sirt1" (AROS) protein. We then studied Sirt1 features such as molecular size, secondary structure, and stimulation by small molecules and AROS. We find that Sirt1 is monomeric and has extended conformations in its flanking domains, likely disordered especially in the N-terminus, resulting in an increased hydrodynamic radius. Nevertheless, both termini increase Sirt1 deacetylase activity, indicating a regulatory function. We also find an unusual but defined conformation for AROS protein, which fails, however, to stimulate Sirt1. Resveratrol, in contrast, activates the Sirt1 catalytic core independent of the terminal domains, indicating a binding site within the catalytic core and suggesting that small molecule activators for other isoforms might also exist.
    Full-text · Article · Apr 2013 · Bioscience Reports
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    • "In each case, the active GAP complex consists of two distinct subunits, of which the catalytic subunit has significant homology with the TSC2 GAP-domain [30-32]. It is possible that such multimeric GAP complexes would be more responsive allosteric regulation [13,14], and therefore more sensitive to changes in upstream signalling events. "
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    ABSTRACT: Background Mutations to the TSC1 and TSC2 genes cause the disease tuberous sclerosis complex. The TSC1 and TSC2 gene products form a protein complex that integrates multiple metabolic signals to regulate the activity of the target of rapamycin (TOR) complex 1 (TORC1) and thereby control cell growth. Here we investigate the quaternary structure of the TSC1-TSC2 complex by gel filtration and coimmunoprecipitation. Results TSC1 and TSC2 co-eluted in high molecular weight fractions by gel filtration. Coimmunoprecipitation of distinct tagged TSC1 and TSC2 isoforms demonstrated that TSC1-TSC2 complexes contain multiple TSC1 and TSC2 subunits. Conclusions TSC1 and TSC2 interact to form large complexes containing multiple TSC1 and TSC2 subunits.
    Full-text · Article · Sep 2012 · BMC Biochemistry
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