Intrinsic Protein Disorder and Interaction Promiscuity Are Widely Associated with Dosage Sensitivity

Vavouri, Tanya; Semple, Jennifer I.; Garcia-Verdugo, Rosa; Liu, Ben

doi:10.1016/s9999-9994(09)20362-x

Cited by 81 publications

(107 citation statements)

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“…The conformational flexibility and biochemical properties of natively unstructured regions, which often contain multiple, short linear peptide motifs for molecular interactions and/or posttranslational modifications (Tompa et al, 2014), specify and fine-tune the assembly of macromolecular complexes via induced and cooperative folding (Babu et al, 2011;Wright and Dyson, 2015). Because intrinsically disordered proteins are prone to engage in promiscuous molecular interactions via peptide motifs of low complexity, their steady-state concentrations are tightly regulated at multiple levels, and elevated gene expression often causes detrimental effects or disease (Vavouri et al, 2009;Babu et al, 2011). While almost nothing is known about the control of IQD gene expression and IQD protein stability, with the exception of IQD22, which is induced rapidly by GA 3 via DELLAdependent regulation (Zentella et al, 2007), it is of note that IQD-related phenotypes have been reported only for IQD-overexpressing plants, which display altered secondary metabolism , cell shape (Figs.…”

Section: Discussionmentioning

confidence: 99%

The IQD Family of Calmodulin-Binding Proteins Links Calcium Signaling to Microtubules, Membrane Subdomains, and the Nucleus

et al. 2017

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ORCID IDs: 0000-0002-3493-4800 (K.B.); 0000-0002-7146-043X (B.M.).Calcium (Ca 2+ ) signaling and dynamic reorganization of the cytoskeleton are essential processes for the coordination and control of plant cell shape and cell growth. Calmodulin (CaM) and closely related calmodulin-like (CML) polypeptides are principal sensors of Ca 2+ signals. CaM/CMLs decode and relay information encrypted by the second messenger via differential interactions with a wide spectrum of targets to modulate their diverse biochemical activities. The plant-specific IQ67 DOMAIN (IQD) family emerged as possibly the largest class of CaM-interacting proteins with undefined molecular functions and biological roles. Here, we show that the 33 members of the IQD family in Arabidopsis (Arabidopsis thaliana) differentially localize, using green fluorescent protein (GFP)-tagged proteins, to multiple and distinct subcellular sites, including microtubule (MT) arrays, plasma membrane subdomains, and nuclear compartments. Intriguingly, the various IQD-specific localization patterns coincide with the subcellular patterns of IQD-dependent recruitment of CaM, suggesting that the diverse IQD members sequester Ca 2+ -CaM signaling modules to specific subcellular sites for precise regulation of Ca 2+ -dependent processes. Because MT localization is a hallmark of most IQD family members, we quantitatively analyzed GFP-labeled MT arrays in Nicotiana benthamiana cells transiently expressing GFP-IQD fusions and observed IQD-specific MT patterns, which point to a role of IQDs in MT organization and dynamics. Indeed, stable overexpression of select IQD proteins in Arabidopsis altered cellular MT orientation, cell shape, and organ morphology. Because IQDs share biochemical properties with scaffold proteins, we propose that IQD families provide an assortment of platform proteins for integrating CaM-dependent Ca 2+ signaling at multiple cellular sites to regulate cell function, shape, and growth.

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Section: Discussionmentioning

confidence: 99%

The IQD Family of Calmodulin-Binding Proteins Links Calcium Signaling to Microtubules, Membrane Subdomains, and the Nucleus

et al. 2017

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“…Given the fact that nearly 20-30% of all proteins in mammalian cells are intrinsically disordered (Dunker et al, 2008) and can engage in promiscuous molecular interactions (Vavouri et al, 2009), cells considerably invest in a number of protein quality control factors to prevent protein misfolding and aggregation. Among these factors, molecular chaperones and degradation machinery of proteostasis play an essential role.…”

Section: Ii44 Cellular Defense Mechanisms Against Protein Misfoldingmentioning

confidence: 99%

Firefly luciferase mutants as sensors of proteome stress

et al. 2011

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“…Second, disease-causing mutations can lead to perturbations in the PPI networks in affected tissues, thereby influencing pathogenesis. Changes in functional protein interactions are frequently linked to changed protein levels in cells; both phenomena have been shown to favor spontaneous protein misfolding and are indicators that a protein might influence HTT aggregation and HD pathogenesis (Pechmann et al 2009;Vavouri et al 2009). Therefore, we reasoned that HTT interaction partners displaying abnormal changes in abundance in regions of the brain that are particularly vulnerable to HD may be disease-relevant modifiers that influence mutant HTT misfolding and aggregation.…”

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confidence: 99%

Systematic interaction network filtering identifies CRMP1 as a novel suppressor of huntingtin misfolding and neurotoxicity

et al. 2015

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Assemblies of huntingtin (HTT) fragments with expanded polyglutamine (polyQ) tracts are a pathological hallmark of Huntington's disease (HD). The molecular mechanisms by which these structures are formed and cause neuronal dysfunction and toxicity are poorly understood. Here, we utilized available gene expression data sets of selected brain regions of HD patients and controls for systematic interaction network filtering in order to predict disease-relevant, brain region-specific HTT interaction partners. Starting from a large protein-protein interaction (PPI) data set, a step-by-step computational filtering strategy facilitated the generation of a focused PPI network that directly or indirectly connects 13 proteins potentially dysregulated in HD with the disease protein HTT. This network enabled the discovery of the neuron-specific protein CRMP1 that targets aggregation-prone, N-terminal HTT fragments and suppresses their spontaneous self-assembly into proteotoxic structures in various models of HD. Experimental validation indicates that our network filtering procedure provides a simple but powerful strategy to identify disease-relevant proteins that influence misfolding and aggregation of polyQ disease proteins.

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Intrinsic Protein Disorder and Interaction Promiscuity Are Widely Associated with Dosage Sensitivity

Cited by 81 publications

References 0 publications

The IQD Family of Calmodulin-Binding Proteins Links Calcium Signaling to Microtubules, Membrane Subdomains, and the Nucleus

The IQD Family of Calmodulin-Binding Proteins Links Calcium Signaling to Microtubules, Membrane Subdomains, and the Nucleus

Firefly luciferase mutants as sensors of proteome stress

Systematic interaction network filtering identifies CRMP1 as a novel suppressor of huntingtin misfolding and neurotoxicity

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