Intrinsically disordered proteins and conformational noise

Mahmoudabadi, Gita; Rajagopalan, Krithika; Getzenberg, Robert H.; Hannenhalli, Sridhar; Rangarajan, Govindan; Kulkarni, Prakash

doi:10.4161/cc.23178

Cited by 53 publications

(73 citation statements)

References 43 publications

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“…8B). Thus, phenotypic plasticity in PCa may be driven by the underlying oscillatory dynamics in the PAGE4/AP-1/AR regulatory circuit rather than by genetic changes alone, supporting the idea that IDP conformational dynamics may play a role in driving state switching (57). Consistent with this argument, a growing number of studies focusing on well-studied systems that have been analyzed using multiple quantitative measurement and perturbation approaches demonstrate that cells can send and receive information by controlling the temporal behavior (dynamics) of their signaling molecules, without involving genetic changes (58).…”

Section: Discussionmentioning

confidence: 72%

Phosphorylation-induced conformational dynamics in an intrinsically disordered protein and potential role in phenotypic heterogeneity

Kulkarni

Jolly

Jia

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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149

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Intrinsically disordered proteins (IDPs) that lack a unique 3D structure and comprise a large fraction of the human proteome play important roles in numerous cellular functions. ProstateAssociated Gene 4 (PAGE4) is an IDP that acts as a potentiator of the Activator Protein-1 (AP-1) transcription factor. HomeodomainInteracting Protein Kinase 1 (HIPK1) phosphorylates PAGE4 at S9 and T51, but only T51 is critical for its activity. Here, we identify a second kinase, CDC-Like Kinase 2 (CLK2), which acts on PAGE4 and hyperphosphorylates it at multiple S/T residues, including S9 and T51. We demonstrate that HIPK1 is expressed in both androgendependent and androgen-independent prostate cancer (PCa) cells, whereas CLK2 and PAGE4 are expressed only in androgendependent cells. Cell-based studies indicate that PAGE4 interaction with the two kinases leads to opposing functions. HIPK1-phosphorylated PAGE4 (HIPK1-PAGE4) potentiates c-Jun, whereas CLK2-phosphorylated PAGE4 (CLK2-PAGE4) attenuates c-Jun activity. Consistent with the cellular data, biophysical measurements (small-angle X-ray scattering, single-molecule fluorescence resonance energy transfer, and NMR) indicate that HIPK1-PAGE4 exhibits a relatively compact conformational ensemble that binds AP-1, whereas CLK2-PAGE4 is more expanded and resembles a random coil with diminished affinity for AP-1. Taken together, the results suggest that the phosphorylation-induced conformational dynamics of PAGE4 may play a role in modulating changes between PCa cell phenotypes. A mathematical model based on our experimental data demonstrates how differential phosphorylation of PAGE4 can lead to transitions between androgen-dependent and androgen-independent phenotypes by altering the AP-1/androgen receptor regulatory circuit in PCa cells.intrinsic disorder | androgen resistance | prostate cancer | PAGE-4 | phenotypic heterogeneity C ontrary to conventional wisdom that structure defines protein function (1), it is now increasingly evident that a large fraction of the human proteome is composed of intrinsically disordered proteins (IDPs) lacking rigid 3D structure (2-4). IDPs exist as conformational ensembles that are highly malleable, facilitating their interactions with multiple partners. These interactions are "wired" to form scale-free networks (5, 6) that represent the main conduit of information flow in the cell. Furthermore, the organization and properties of such protein interaction networks are evolutionarily conserved, underscoring their functional significance (7).By occupying hub positions in such networks, IDPs play critical roles in many biological processes, such as transcription, translation, and signaling (8, 9). IDPs also participate in higher order phenomena, such as regulation of the cell division cycle (10-12), circadian rhythmicity (13, 14), and phenotypic plasticity (15, 16). Recent evidence suggests that several IDPs can act in a prion-like manner to create protein-based molecular memories that drive the emergence and inheritance of biological traits (17), furt...

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Section: Discussionmentioning

confidence: 72%

Phosphorylation-induced conformational dynamics in an intrinsically disordered protein and potential role in phenotypic heterogeneity

Kulkarni

Jolly

Jia

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

149

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“…From a fundamental perspective, recent research on IDPs and how they might contribute to pathological states when overexpressed suggests that noise in PINs contributed by the conformational dynamics of IDPs plays a critical role in information transfer in cancer[32]. Since many IDPs transition from disorder to order upon binding to their target, stochasticity of IDP interactions allows the system to search through numerous iterations of network interactions and select those that increase fitness.…”

Section: Discussionmentioning

confidence: 99%

“…Since many IDPs transition from disorder to order upon binding to their target, stochasticity of IDP interactions allows the system to search through numerous iterations of network interactions and select those that increase fitness. Rewiring of noise-driven PINs can activate latent pathways that drive cellular transformation and adaptation [32]. Thus, given the potential for conformational flexibility, PAGE4 could rewire PINs by interacting with multiple partners and drive cellular transformation.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, noise may be considered an integral part of the correct transmission of signals and signaling cascades including those that play a role in the fidelity of epigenetic memory [31]. We recently hypothesized that noise due to IDP conformational dynamics can rewire PINs to cause phenotypic switching such as the transformation of a normal cell to a cancer cell [32]. Because noise affects central regulatory switches in cell functions, it is plausible that alterations in noise level could induce pathological states such as cancer [31].…”

Section: Introductionmentioning

confidence: 99%

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The Stress-response protein prostate-associated gene 4, interacts with c-Jun and potentiates its transactivation

Rajagopalan

Qiu

Mooney

et al. 2014

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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The Cancer/Testis Antigen (CTA), Prostate-associated Gene 4 (PAGE4), is a stress-response protein that is upregulated in prostate cancer (PCa) especially in precursor lesions that result from inflammatory stress. In cells under stress, translocation of PAGE4 to mitochondria increases while production of reactive oxygen species decreases. Furthermore, PAGE4 is also upregulated in human fetal prostate, underscoring its potential role in development. However, the proteins that interact with PAGE4 and the mechanisms underlying its pleiotropic functions in prostatic development and disease remain unknown. Here, we identified c-Jun as a PAGE4 interacting partner. We show that both PAGE4 and c-Jun are overexpressed in the human fetal prostate; and in cell-based assays, PAGE4 robustly potentiates c-Jun transactivation. Single-molecule Förster resonance energy transfer experiments indicate that upon binding to c-Jun, PAGE4 undergoes conformational changes. However, no interaction is observed in presence of BSA or unilamellar vesicles containing the mitochondrial inner membrane diphosphatidylglycerol lipid marker cardiolipin. Together, our data indicate that PAGE4 specifically interacts with c-Jun and that, conformational dynamics may account for its observed pleiotropic functions. To our knowledge, this is the first report demonstrating crosstalk between a CTA and a proto-oncogene. Disrupting PAGE4/c-Jun interactions using small molecules may represent a novel therapeutic strategy for PCa.

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“…Being IDPs, the structural plasticity of CTAs could also contribute significantly to “noise” in the PINs, especially when they are overexpressed 9. Recent progress has revealed that many biological processes are driven by probabilistic events underscoring the importance of “noise” in biological systems 10.…”

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confidence: 99%

Cancer/testis antigens and obligate participation in multiple hallmarks of cancer: an update

et al. 2016

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The Cancer/Testis Antigens (CTAs) are a group of so-called tumor antigens that exhibit provocative expression patterns in most types of cancer. However, because most CTAs appear to be intrinsically disordered, they are recalcitrant to classical structural studies. Thus, the functions of most, if not all, CTAs have remained elusive and their potential as pharmacological targets in cancer has remained largely unexplored. In this viewpoint, we suggest that perhaps, an integrative approach applying dynamical systems theory and a system-level perspective rather a merely reductionist view, may shine new light on these enigmatic molecules.

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Intrinsically disordered proteins and conformational noise

Cited by 53 publications

References 43 publications

Phosphorylation-induced conformational dynamics in an intrinsically disordered protein and potential role in phenotypic heterogeneity

Phosphorylation-induced conformational dynamics in an intrinsically disordered protein and potential role in phenotypic heterogeneity

The Stress-response protein prostate-associated gene 4, interacts with c-Jun and potentiates its transactivation

Cancer/testis antigens and obligate participation in multiple hallmarks of cancer: an update

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