p53 Proteoforms and Intrinsic Disorder: An Illustration of the Protein Structure–Function Continuum Concept

Uversky, Vladimir N.

doi:10.3390/ijms17111874

Cited by 165 publications

(135 citation statements)

References 253 publications

(377 reference statements)

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“…In fact, AS was indicated as one of the cellular mechanisms (such as chromosomal translocations, altered expression, PTMs, aberrant proteolytic degradation and defective trafficking) that might cause pathogenic transformations in IDPs [148]. Furthermore, the indicated structural plasticity and multifunctionality of PAGE4, NOL4 and CEP55 are in line with the proteoform concept, according to which a functional protein product of a single gene exists in different molecular forms generated by genetic variations, alternative splicing and PTMs [149], as well as by intrinsic conformational plasticity and as a result of protein functioning [150]. …”

Section: Discussionmentioning

confidence: 99%

Cancer/Testis Antigens: “Smart” Biomarkers for Diagnosis and Prognosis of Prostate and Other Cancers

Kulkarni

Uversky

2017

IJMS

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A clinical dilemma in the management of prostate cancer (PCa) is to distinguish men with aggressive disease who need definitive treatment from men who may not require immediate intervention. Accurate prediction of disease behavior is critical because radical treatment is associated with high morbidity. Here, we highlight the cancer/testis antigens (CTAs) as potential PCa biomarkers. The CTAs are a group of proteins that are typically restricted to the testis in the normal adult but are aberrantly expressed in several types of cancers. Interestingly, >90% of CTAs are predicted to belong to the realm of intrinsically disordered proteins (IDPs), which do not have unique structures and exist as highly dynamic conformational ensembles, but are known to play important roles in several biological processes. Using prostate-associated gene 4 (PAGE4) as an example of a disordered CTA, we highlight how IDP conformational dynamics may regulate phenotypic heterogeneity in PCa cells, and how it may be exploited both as a potential biomarker as well as a promising therapeutic target in PCa. We also discuss how in addition to intrinsic disorder and post-translational modifications, structural and functional variability induced in the CTAs by alternate splicing represents an important feature that might have different roles in different cancers. Although it is clear that significant additional work needs to be done in the outlined direction, this novel concept emphasizing (multi)functionality as an important trait in selecting a biomarker underscoring the theranostic potential of CTAs that is latent in their structure (or, more appropriately, the lack thereof), and casts them as next generation or “smart” biomarker candidates.

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Section: Discussionmentioning

confidence: 99%

Cancer/Testis Antigens: “Smart” Biomarkers for Diagnosis and Prognosis of Prostate and Other Cancers

Kulkarni

Uversky

2017

IJMS

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“…So far, studies on IDPs/IDRs have greatly extended our understanding on the sequence–structure–function relationship of proteins . Recently, the protein structure–function continuum concept was proposed by Uversky to illustrate the numerous biological functions of p53 through multiple proteoforms by various mechanisms and may be extended to many multi‐function IDPs …”

Section: Introductionmentioning

confidence: 99%

Features of molecular recognition of intrinsically disordered proteins via coupled folding and binding

et al. 2019

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The sequence–structure–function paradigm of proteins has been revolutionized by the discovery of intrinsically disordered proteins (IDPs) or intrinsically disordered regions (IDRs). In contrast to traditional ordered proteins, IDPs/IDRs are unstructured under physiological conditions. The absence of well‐defined three‐dimensional structures in the free state of IDPs/IDRs is fundamental to their function. Folding upon binding is an important mode of molecular recognition for IDPs/IDRs. While great efforts have been devoted to investigating the complex structures and binding kinetics and affinities, our knowledge on the binding mechanisms of IDPs/IDRs remains very limited. Here, we review recent advances on the binding mechanisms of IDPs/IDRs. The structures and kinetic parameters of IDPs/IDRs can vary greatly, and the binding mechanisms can be highly dependent on the structural properties of IDPs/IDRs. IDPs/IDRs can employ various combinations of conformational selection and induced fit in a binding process, which can be templated by the target and/or encoded by the IDP/IDR. Further studies should provide deeper insights into the molecular recognition of IDPs/IDRs and enable the rational design of IDP/IDR binding mechanisms in the future.

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“…It is a key regulatory protein, especially as a transcription factor, and participates in diverse cellular processes, such as cell cycle arrest, DNA repair, and apoptosis. 1,[6][7][8][9][10][11][12][13][14] Constitutive synthesis and degradation maintain low levels of p53 in unstressed cells, but provide a mechanism for the rapid increase in cellular p53 levels in response to stress through inhibition of p53 degradation. 5 Activities of p53, such as efficient and specific binding to p53 cis-elements within target promoter sequences, as well as tissue-, time-, and stimulus-specific binding of numerous coactivators and modifiers, are regulated by its abundance, post-translational modifications, and protein-protein interactions; all of which are influenced by a number of signaling pathways converging on p53.…”

Section: Introductionmentioning

confidence: 99%

Calpain-mediated cleavage of p53 in human cytomegalovirus-infected lung fibroblasts

et al. 2018

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Endogenous fragments of p53 protein were identified in human cytomegalovirus (HCMV)‐infected human lung fibroblasts, particularly a 44‐kDa N‐terminal fragment [hereafter referred to as p53(ΔCp44)], generated via calpain cleavage. The fragment abundance increased in a biphasic manner, peaking at 6‐9 hours and 48 hours post infection. Treatment of LU cells with calpain inhibitors eliminated most detectable p53 fragments. In cell‐free experiments, exogenous m‐calpain cleavage generated p53(ΔCp44). Attempts to preserve p53 proteins by treating cells with the calpain inhibitor E64d for 6 hours before harvesting increased the sensitivity of p53 to calpain cleavage. p53 in mock‐infected cell lysates was much more sensitive to cleavage and degradation by exogenous calpain than that in HCMV‐infected cells. The proteasome inhibitor MG132 stabilized p53(ΔCp44), particularly in mock‐infected cells. p53(ΔCp44) appeared to be tightly associated with a chromatin‐rich fraction. The abundance of p53β was unchanged over a 96‐h time course and very similar in mock‐ and HCMV‐infected cells, making it unlikely that p53(ΔCp44) was p53β. The biological activities of this and other fragments lacking C‐terminal sequences are unknown, but deserve further investigation, given the association of p53(ΔCp44) with the chromatin‐rich (or buffer C insoluble) fraction in HCMV‐infected cells.

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p53 Proteoforms and Intrinsic Disorder: An Illustration of the Protein Structure–Function Continuum Concept

Cited by 165 publications

References 253 publications

Cancer/Testis Antigens: “Smart” Biomarkers for Diagnosis and Prognosis of Prostate and Other Cancers

Cancer/Testis Antigens: “Smart” Biomarkers for Diagnosis and Prognosis of Prostate and Other Cancers

Features of molecular recognition of intrinsically disordered proteins via coupled folding and binding

Calpain-mediated cleavage of p53 in human cytomegalovirus-infected lung fibroblasts

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