Browsing by Subject "Intrinsically disordered protein"

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    A creature with a hundred waggly tails: intrinsically disordered proteins in the ribosome
    (Springer Nature, 2014) Peng, Zhenling; Oldfield, Christopher J.; Xue, Bin; Mizianty, Marcin J.; Dunker, A. Keith; Kurgan, Lukasz; Uversky, Vladmir N.; Biochemistry & Molecular Biology, IU School of Medicine
    Intrinsic disorder (i.e., lack of a unique 3-D structure) is a common phenomenon, and many biologically active proteins are disordered as a whole, or contain long disordered regions. These intrinsically disordered proteins/regions constitute a significant part of all proteomes, and their functional repertoire is complementary to functions of ordered proteins. In fact, intrinsic disorder represents an important driving force for many specific functions. An illustrative example of such disorder-centric functional class is RNA-binding proteins. In this study, we present the results of comprehensive bioinformatics analyses of the abundance and roles of intrinsic disorder in 3,411 ribosomal proteins from 32 species. We show that many ribosomal proteins are intrinsically disordered or hybrid proteins that contain ordered and disordered domains. Predicted globular domains of many ribosomal proteins contain noticeable regions of intrinsic disorder. We also show that disorder in ribosomal proteins has different characteristics compared to other proteins that interact with RNA and DNA including overall abundance, evolutionary conservation, and involvement in protein–protein interactions. Furthermore, intrinsic disorder is not only abundant in the ribosomal proteins, but we demonstrate that it is absolutely necessary for their various functions.
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    A creature with a hundred waggly tails: intrinsically disordered proteins in the ribosome
    (Springer, 2013-08-13) Peng, Zhenling; Oldfield, Christopher J.; Xue, Bin; Mizianty, Marcin J.; Dunker, A. Keith; Kurgan, Lukasz; Uversky, Vladimir N.; Biochemistry and Molecular Biology, School of Medicine
    Intrinsic disorder (i.e., lack of a unique 3-D structure) is a common phenomenon, and many biologically active proteins are disordered as a whole, or contain long disordered regions. These intrinsically disordered proteins/regions constitute a significant part of all proteomes, and their functional repertoire is complementary to functions of ordered proteins. In fact, intrinsic disorder represents an important driving force for many specific functions. An illustrative example of such disorder-centric functional class is RNA-binding proteins. In this study, we present the results of comprehensive bioinformatics analyses of the abundance and roles of intrinsic disorder in 3,411 ribosomal proteins from 32 species. We show that many ribosomal proteins are intrinsically disordered or hybrid proteins that contain ordered and disordered domains. Predicted globular domains of many ribosomal proteins contain noticeable regions of intrinsic disorder. We also show that disorder in ribosomal proteins has different characteristics compared to other proteins that interact with RNA and DNA including overall abundance, evolutionary conservation, and involvement in protein–protein interactions. Furthermore, intrinsic disorder is not only abundant in the ribosomal proteins, but we demonstrate that it is absolutely necessary for their various functions.
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    Mechanisms of binding diversity in protein disorder : molecular recognition features mediating protein interaction networks
    (2013-07) Hsu, Wei-Lun; Dunker, A. Keith; Zhou, Yaoqi; Hurley, Thomas D., 1961-; Uversky, Vladimir N.
    Intrinsically disordered proteins are proteins characterized by lack of stable tertiary structures under physiological conditions. Evidence shows that disordered proteins are not only highly involved in protein interactions, but also have the capability to associate with more than one partner. Short disordered protein fragments, called “molecular recognition features” (MoRFs), were hypothesized to facilitate the binding diversity of highly-connected proteins termed “hubs”. MoRFs often couple folding with binding while forming interaction complexes. Two protein disorder mechanisms were proposed to facilitate multiple partner binding and enable hub proteins to bind to multiple partners: 1. One region of disorder could bind to many different partners (one-to-many binding), so the hub protein itself uses disorder for multiple partner binding; and 2. Many different regions of disorder could bind to a single partner (many-to-one binding), so the hub protein is structured but binds to many disordered partners via interaction with disorder. Thousands of MoRF-partner protein complexes were collected from Protein Data Bank in this study, including 321 one-to-many binding examples and 514 many-to-one binding examples. The conformational flexibility of MoRFs was observed at atomic resolution to help the MoRFs to adapt themselves to various binding surfaces of partners or to enable different MoRFs with non-identical sequences to associate with one specific binding pocket. Strikingly, in one-to-many binding, post-translational modification, alternative splicing and partner topology were revealed to play key roles for partner selection of these fuzzy complexes. On the other hand, three distinct binding profiles were identified in the collected many-to-one dataset: similar, intersecting and independent. For the similar binding profile, the distinct MoRFs interact with almost identical binding sites on the same partner. The MoRFs can also interact with a partially the same but partially different binding site, giving the intersecting binding profile. Finally, the MoRFs can interact with completely different binding sites, thus giving the independent binding profile. In conclusion, we suggest that protein disorder with post-translational modifications and alternative splicing are all working together to rewire the protein interaction networks.
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    Prostate-associated gene 4 (PAGE4), an intrinsically disordered cancer/testis antigen, is a novel therapeutic target for prostate cancer
    (Wolters Kluwer, 2016) Kulkarni, Prakash; Dunker, A. Keith; Weninger, Keith; Orban, John; Department of Biochemistry and Molecular Biology, IU School of Medicine
    Prostate-associated gene 4 (PAGE4) is a remarkably prostate-specific Cancer/Testis Antigen that is highly upregulated in the human fetal prostate and its diseased states but not in the adult normal gland. PAGE4 is an intrinsically disordered protein (IDP) that functions as a stress-response protein to suppress reactive oxygen species as well as prevent DNA damage. In addition, PAGE4 is also a transcriptional regulator that potentiates transactivation by the oncogene c-Jun. c-Jun forms the AP-1 complex by heterodimerizing with members of the Fos family and plays an important role in the development and pathology of the prostate gland, underscoring the importance of the PAGE4/c-Jun interaction. HIPK1, also a component of the stress-response pathway, phosphorylates PAGE4 at T51 which is critical for its transcriptional activity. Phosphorylation induces conformational and dynamic switching in the PAGE4 ensemble leading to a new cellular function. Finally, bioinformatics evidence suggests that the PAGE4 mRNA could be alternatively spliced resulting in four potential isoforms of the polypeptide alluding to the possibility of a range of conformational ensembles with latent functions. Considered together, the data suggest that PAGE4 may represent the first molecular link between stress and prostate cancer (PCa). Thus, pharmacologically targeting PAGE4 may be a novel opportunity for treating and managing patients with PCa, especially patients with low-risk disease.
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    Shell disorder analysis predicts greater resilience of the SARS-CoV-2 (COVID-19) outside the body and in body fluids
    (Elsevier, 2020-07) Goh, Gerard Kian-Meng; Dunker, A. Keith; Foster, James A.; Uversky, Vladimir N.; Biochemistry and Molecular Biology, School of Medicine
    The coronavirus (CoV) family consists of viruses that infects a variety of animals including humans with various levels of respiratory and fecal-oral transmission levels depending on the behavior of the viruses' natural hosts and optimal viral fitness. A model to classify and predict the levels of respective respiratory and fecal-oral transmission potentials of the various viruses was built before the outbreak of MERS-CoV using AI and empirically-based molecular tools to predict the disorder level of proteins. Using the percentages of intrinsic disorder (PID) of the nucleocapsid (N) and membrane (M) proteins of CoV, the model easily clustered the viruses into three groups with the SARS-CoV (M PID = 8%, N PID = 50%) falling into Category B, in which viruses have intermediate levels of both respiratory and fecal-oral transmission potentials. Later, MERS-CoV (M PID = 9%, N PID = 44%) was found to be in Category C, which consists of viruses with lower respiratory transmission potential but with higher fecal-oral transmission capabilities. Based on the peculiarities of disorder distribution, the SARS-CoV-2 (M PID = 6%, N PID = 48%) has to be placed in Category B. Our data show however, that the SARS-CoV-2 is very strange with one of the hardest protective outer shell, (M PID = 6%) among coronaviruses. This means that it might be expected to be highly resilient in saliva or other body fluids and outside the body. An infected body is likelier to shed greater numbers of viral particles since the latter is more resistant to antimicrobial enzymes in body fluids. These particles are also likelier to remain active longer. These factors could account for the greater contagiousness of the SARS-CoV-2 and have implications for efforts to prevent its spread.
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    The structural and functional signatures of proteins that undergo multiple events of post-translational modification
    (Wiley, 2014-08) Pejaver, Vikas; Hsu, Wei-Lun; Dunker, A. Keith; Uversky, Vladimir N.; Radivojac, Predrag; Biochemistry & Molecular Biology, School of Medicine
    The structural, functional, and mechanistic characterization of several types of post-translational modifications (PTMs) is well-documented. PTMs, however, may interact or interfere with one another when regulating protein function. Yet, characterization of the structural and functional signatures of their crosstalk has been hindered by the scarcity of data. To this end, we developed a unified sequence-based predictor of 23 types of PTM sites that, we believe, is a useful tool in guiding biological experiments and data interpretation. We then used experimentally determined and predicted PTM sites to investigate two particular cases of potential PTM crosstalk in eukaryotes. First, we identified proteins statistically enriched in multiple types of PTM sites and found that they show preferences toward intrinsically disordered regions as well as functional roles in transcriptional, posttranscriptional, and developmental processes. Second, we observed that target sites modified by more than one type of PTM, referred to as shared PTM sites, show even stronger preferences toward disordered regions than their single-PTM counterparts; we explain this by the need for these regions to accommodate multiple partners. Finally, we investigated the influence of single and shared PTMs on differential regulation of protein-protein interactions. We provide evidence that molecular recognition features (MoRFs) show significant preferences for PTM sites, particularly shared PTM sites, implicating PTMs in the modulation of this specific type of macromolecular recognition. We conclude that intrinsic disorder is a strong structural prerequisite for complex PTM-based regulation, particularly in context-dependent protein-protein interactions related to transcriptional and developmental processes.