The structural and functional signatures of proteins that undergo multiple events of post‐translational modification
Open accessAbstract
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. Availability: www.modpred.org
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Experiments and predictions indicate that for all of these proteins the multiple PTMs are located in IDRs.
“Experiments and predictions indicate that for all of these proteins the multiple PTMs are located in IDRs [52].”
From Intrinsically disordered proteins play diverse roles in cell signaling (2022) · cites this paper as [52]
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Serrano-Gomez, S. J., Maziveyi, M., & Alahari, S. K. (2016) · Molecular Cancer · doi:10.1186/s12943-016-0502-x · Cited by 817 · see citing works
Mechanistic insights into mammalian stress granule dynamics
Panas, M. D., Ivanov, P. V., & Anderson, P. (2016) · The Journal of Cell Biology · doi:10.1083/jcb.201609081 · Cited by 374 · see citing works
“Their conformation can also be modulated by post-translational modifications (PTMs) found within or in close proximity to IDPRs, allowing context-dependent modulation of their structure (Iakoucheva et al., 2004; Pejaver et al., 2014).”
BackgroundWang, D., Liu, D., Yuchi, J., He, F., Jiang, Y., Cai, S., Li, J., & Xu, D. H. (2020) · Nucleic Acids Research · doi:10.1093/nar/gkaa275 · Cited by 316 · see citing works
“ModPred (20) provides a general webserver for 23 different modifications.”
Wang, D.-L., Zeng, S., Xu, C., Qiu, W.-R., Liang, Y., Joshi, T., & Xu, D. (2017) · Bioinform. · doi:10.1093/bioinformatics/btx496 · Cited by 255 · see citing works
Darling, A., & Uversky, V. (2018) · Frontiers in Genetics · doi:10.3389/fgene.2018.00158 · Cited by 236 · see citing works
“These proteins affected by more than one PTM are commonly involved in transcriptional, posttranscriptional, and developmental processes contain multiPTM or shared-PTM display sites that are characterized by preferences toward IDPRs exceeding those of the single-PTM sites (Pejaver et al., 2014).”
BackgroundInfluentialSelf-citationNickel impact on human health: An intrinsic disorder perspective
Zambelli, B., Uversky, V. N., & Ciurli, S. (2016) · Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics · doi:10.1016/j.bbapap.2016.09.008 · Cited by 253 · see citing works
Self-citationUversky, V. N. (2016) · Advances in Colloid and Interface Science · doi:10.1016/j.cis.2016.05.012 · Cited by 233 · see citing works
Self-citationIntrinsically disordered proteins play diverse roles in cell signaling
Bondos, S. E., Dunker, A. K., & Uversky, V. N. (2022) · Cell Communication and Signaling · doi:10.1186/s12964-022-00821-7 · Cited by 222 · see citing works
“and sites of proteolytic attack are often associated with regions of intrinsic disorder [3, 52].”
BackgroundSelf-citationIntrinsically Disordered Proteome of Human Membrane‐Less Organelles
Darling, A. L., Liu, Y., Oldfield, C. J., & Uversky, V. N. (2017) · PROTEOMICS · doi:10.1002/pmic.201700193 · Cited by 218 · see citing works
Self-citationFunctional roles of transiently and intrinsically disordered regions within proteins
Uversky, V. N. (2015) · FEBS Journal · doi:10.1111/febs.13202 · Cited by 215 · see citing works
Self-citationDancing Protein Clouds: The Strange Biology and Chaotic Physics of Intrinsically Disordered Proteins
Uversky, V. N. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.r115.685859 · Cited by 212 · see citing works
“Therefore, IDPRs serve as carriers of PTMs, with disorder being especially important for regions undergoing multiple PTM events (29).”
BackgroundSelf-citationIntrinsically disordered proteins and their (disordered) proteomes in neurodegenerative disorders
Uversky, V. N. (2015) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2015.00018 · Cited by 204 · see citing works
“…means of extensive posttranslational modifications (PTMs), such as phosphorylation, acetylation, glycosylation (Collins et al., 2008; Uversky and Dunker, 2010; Kurotani et al., 2014; Pejaver et al., 2014), and by alternative splicing (Romero et al., 2006; Buljan et al., 2012, 2013; Uversky, 2014b).”
BackgroundSelf-citationUversky, V. N. (2016) · International Journal of Molecular Sciences · doi:10.3390/ijms17111874 · Cited by 193 · see citing works
“Since many PTM sites are known to be preferentially found within the regions of intrinsic disorder [46,47], since mRNA regions affected by alternative splicing predominantly encodes IDPRs [48], and since IDPs/IDPRs are known to be highly promiscuous binders [4,6,7,12–15,20–24,28,29,49–55], disordered proteins represen…”
BackgroundSelf-citationProtein post-translational modifications: In silico prediction tools and molecular modeling
Audagnotto, M., & Peraro, M. D. (2017) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2017.03.004 · Cited by 189 · see citing works
“The first unified tool for a simultaneous prediction of PTM sites wasModPred [296], which predicts and”
MethodFunctional advantages of dynamic protein disorder
Berlow, R. B., Dyson, H. J., & Wright, P. E. (2015) · FEBS Letters · doi:10.1016/j.febslet.2015.06.003 · Cited by 181 · see citing works
“While a single post-translational modification can be a sufficient signal in regulatory processes, PTM sites are often located in clusters within IDPs [85].”
Machine learning meets omics: applications and perspectives
Li, R., Li, L., Xu, Y., & Yang, J. (2021) · Briefings in Bioinformatics · doi:10.1093/bib/bbab460 · Cited by 180 · see citing works
Molecular recognition features (MoRFs) in three domains of life
Yan, J. R., Dunker, A. K., Uversky, V. N., & Kurgan, L. (2015) · Molecular BioSystems · doi:10.1039/c5mb00640f · Cited by 164 · see citing works
Self-citationMore than a marker: potential pathogenic functions of MAP2
DeGiosio, R. A., Grubisha, M. J., MacDonald, M. L., McKinney, B. C., Camacho, C. J., & Sweet, R. A. (2022) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2022.974890 · Cited by 163 · see citing works
Protein intrinsic disorder and structure-function continuum
Uversky, V. N. (2019) · Progress in molecular biology and translational science · doi:10.1016/bs.pmbts.2019.05.003 · Cited by 155 · see citing works
Self-citationIntrinsically disordered proteins and multicellular organisms
Dunker, A. K., Bondos, S. E., Huang, F., & Oldfield, C. J. (2015) · Seminars in Cell & Developmental Biology · doi:10.1016/j.semcdb.2014.09.025 · Cited by 150 · see citing works
Self-citationWen, B., Zeng, W., Liao, Y., Shi, Z., Savage, S. R., Jiang, W., & Zhang, B. (2020) · PROTEOMICS · doi:10.1002/pmic.201900335 · Cited by 152 · see citing works
Deiana, A., Forcelloni, S., Porrello, A., & Giansanti, A. (2019) · PLoS ONE · doi:10.1371/journal.pone.0217889 · Cited by 137 · see citing works
“It has been reported that 94 disordered regions have many post-translational modification sites (PTMs) [8,29,39-41], which 95 induce conformational changes leading to one-lock-many-keys interactions [33].”
BackgroundSharma, V., Srinivasan, A., Nikolajeff, F. K., & Kumar, S. (2020) · Acta Biomaterialia · doi:10.1016/j.actbio.2020.04.049 · Cited by 142 · see citing works
Eukaryotic transcription factors: paradigms of protein intrinsic disorder
Staby, L., O’Shea, C., Willemoës, M., Theisen, F. F., Kragelund, B. B., & Skriver, K. (2017) · Biochemical Journal · doi:10.1042/bcj20160631 · Cited by 134 · see citing works
Capsule network for protein post-translational modification site prediction
Wang, D., Liang, Y., & Xu, D. H. (2018) · Bioinformatics · doi:10.1093/bioinformatics/bty977 · Cited by 139 · see citing works
Niklas, K. J., Bondos, S. E., Dunker, A. K., & Newman, S. A. (2015) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2015.00008 · Cited by 132 · see citing works
“…Bicoid is essential for the correct spatial positioning of eve stripe 2, and the latter’s target CREs in the stripe 2 eve enhancer are well-characterized (Ludwig et al., 2011), studies have shown that disrupted, unstable, and highly abnormal Bicoid gradients fail to disturb the precision of this…”
BackgroundSelf-citationExpanding the Paradigm: Intrinsically Disordered Proteins and Allosteric Regulation
Berlow, R. B., Dyson, H. J., & Wright, P. E. (2018) · Journal of Molecular Biology · doi:10.1016/j.jmb.2018.04.003 · Cited by 129 · see citing works
Antifeeva, I. A., Fonin, A. V., Fefilova, A. S., Stepanenko, O. V., Povarova, O. I., Silonov, S. A., Kuznetsova, I. М., Uversky, V. N., & Константинович, Т. К. (2022) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-022-04276-4 · Cited by 136 · see citing works
Self-citationComplex regulatory mechanisms mediated by the interplay of multiple post-translational modifications
Csizmók, V., & Forman-Kay, J. D. (2017) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2017.10.013 · Cited by 126 · see citing works
Lieutaud, P., Ferrón, F., Uversky, A. V., Kurgan, L., Uversky, V. N., & Longhi, S. (2016) · Intrinsically Disordered Proteins · doi:10.1080/21690707.2016.1259708 · Cited by 125 · see citing works
“This tool represents a very useful instrument for guiding biological experiments and data interpretation.(99)”
BackgroundMethodInfluentialSelf-citationIntrinsic Disorder, Protein–Protein Interactions, and Disease
Uversky, V. N. (2017) · Advances in protein chemistry and structural biology · doi:10.1016/bs.apcsb.2017.06.005 · Cited by 118 · see citing works
Self-citationMeng, F., Na, I., Kurgan, L., & Uversky, V. N. (2015) · International Journal of Molecular Sciences · doi:10.3390/ijms17010024 · Cited by 116 · see citing works
“The fact that disordered domains/regions of these nuclear proteins have several posttranslational modification sites is in agreement with the well-known fact that phosphorylation [76] and many other enzymatically catalyzed posttranslational modifications are preferentially located within the IDPRs [77].”
BackgroundSelf-citationUversky, V. N. (2021) · Annual Review of Biophysics · doi:10.1146/annurev-biophys-062920-063704 · Cited by 117 · see citing works
Self-citationWhy do eukaryotic proteins contain more intrinsically disordered regions?
Basile, W., Salvatore, M., Bassot, C., & Elofsson, A. (2019) · PLOS Computational Biology · doi:10.1371/journal.pcbi.1007186 · Cited by 113 · see citing works
“One of the functions for disordered regions in proteins is to present short linear motifs that are important for binding [16], further post-translational modification, in particular, phosphorylation, is a fundamental mechanism in the regulation of eukaryotic cell differentiation, as well as many other processes [34] a…”
BackgroundTargeting Intrinsically Disordered Transcription Factors: Changing the Paradigm
Tsafou, K., Tiwari, P. B., Forman-Kay, J. D., Metallo, S. J., & Toretsky, J. A. (2018) · Journal of Molecular Biology · doi:10.1016/j.jmb.2018.04.008 · Cited by 110 · see citing works
Intrinsically disordered proteins in crowded milieu: when chaos prevails within the cellular gumbo
Fonin, A. V., Darling, A. L., Kuznetsova, I. М., Константинович, Т. К., & Uversky, V. N. (2018) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-018-2894-9 · Cited by 107 · see citing works
Self-citationUversky, V. N. (2014) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2014.00006 · Cited by 107 · see citing works
“…regulated by extensive posttranslational modifications (PTMs), such as phosphorylation, acetylation, glycosylation, etc. (Collins et al., 2008; Uversky and Dunker, 2010; Kurotani et al., 2014; Pejaver et al., 2014), and by alternative splicing (AS) (Romero et al., 2006; Buljan et al., 2012, 2013).”
BackgroundSelf-citationHu, G., Wu, Z., Uversky, V. N., & Kurgan, L. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18122761 · Cited by 105 · see citing works
“Furthermore, in line with our observations in this study, biological activities of IDPs/IDPRs can be precisely and tightly controlled and regulated by various PTMs [21,77,94,95] and by alternative splicing (AS) [29,96,97].”
BackgroundMethodInfluentialSelf-citationDarling, A. L., Zaslavsky, B. Y., & Uversky, V. N. (2019) · Polymers · doi:10.3390/polym11060990 · Cited by 96 · see citing works
“Furthermore, structural ‘floppiness’ also defines the ability of IDP/IDPR to be controlled and regulated at multiple levels [21,26,35–37], with various post-translational modifications (PTMs) being one of the most important means of such disorder-centered regulation [38,39].”
BackgroundSelf-citationZhou, X., Sumrow, L., Tashiro, K., Sutherland, L. B., Liu, D., Qin, T., Kato, M., Liszczak, G., & McKnight, S. L. (2022) · Science · doi:10.1126/science.abn5582 · Cited by 96 · see citing works
Pagel, K. A., Pejaver, V. R., Lin, G. N., Nam, H.-J., Mort, M. E., Cooper, D. N., Sebat, J. L., Iakoucheva, L. M., Mooney, S. D., & Predrag Radivojac, A. (2017) · Bioinformatics · doi:10.1093/bioinformatics/btx272 · Cited by 88 · see citing works
Self-citationGupta, M. N., & Uversky, V. N. (2023) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2023.128646 · Cited by 92 · see citing works
Self-citationFonin, A. V., Darling, A. L., Kuznetsova, I. M., Turoverov, K. K., & Uversky, V. N. (2019) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-019-03276-1 · Cited by 91 · see citing works
Self-citationZhou, J., Zhao, S., & Dunker, A. K. (2018) · Journal of Molecular Biology · doi:10.1016/j.jmb.2018.03.028 · Cited by 90 · see citing works
Self-citationYang, J., Gao, M., Xiong, J., Su, Z., & Huang, Y. (2019) · Protein Science · doi:10.1002/pro.3718 · Cited by 85 · see citing works
“(PTM) sites, such as phosphorylation, acetylation, and methylation.(16,194,195) PTMs can regulate molecular recognition of IDPs/IDRs in various ways.”
BackgroundHallmarks of cellular senescence: biology, mechanisms, regulations
Ajoolabady, A., Praticò, D., Bahijri, S., Tuomilehto, J. O., Uversky, V. N., & Ren, J. T. (2025) · Experimental & Molecular Medicine · doi:10.1038/s12276-025-01480-7 · Cited by 95 · see citing works
Self-citationZaslavsky, B. Y., & Uversky, V. N. (2018) · Biochemistry · doi:10.1021/acs.biochem.7b01215 · Cited by 87 · see citing works
Self-citationIntrinsically Disordered Side of the Zika Virus Proteome
Giri, R., Kumar, D., Sharma, N., & Uversky, V. N. (2016) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2016.00144 · Cited by 84 · see citing works
“In fact, sites of various enzymatically-catalyzed posttranslationalmodifications in proteins are commonly located within their IDPRs (Iakoucheva et al., 2004; Pejaver et al., 2014).”
BackgroundSelf-citationIntrinsically Disordered Proteins: The Dark Horse of the Dark Proteome
Kulkarni, P., & Uversky, V. (2018) · Proteomics · doi:10.1002/pmic.201800061 · Cited by 79 · see citing works
Self-citationPagel, K. A., Antaki, D., Lian, A., Mort, M. E., Cooper, D. N., Sebat, J. L., Iakoucheva, L. M., Mooney, S. D., & Predrag Radivojac, A. (2019) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1007112 · Cited by 79 · see citing works
Ferroptosis – An iron- and disorder-dependent programmed cell death
Djulbegovic, M. B., & Uversky, V. N. (2019) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2019.05.221 · Cited by 78 · see citing works
Self-citationThe role of post‐translational modifications in cardiac hypertrophy
Yan, K., Wang, K., & Li, P. (2019) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.14330 · Cited by 77 · see citing works
Uversky, V. N. (2017) · Autophagy · doi:10.1080/15548627.2017.1384889 · Cited by 76 · see citing works
“More recently, another tool has been developed which is a unified sequence-based predictor of 23 types of posttranslational modification (PTM) sites.(69)”
BackgroundMethodSelf-citationEvolution of intrinsic disorder in eukaryotic proteins
Ahrens, J. B., Nunez-Castilla, J., & Siltberg-Liberles, J. (2017) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-017-2559-0 · Cited by 72 · see citing works
“In accordance with the extended conformational selection processes, binding events ranging from lock-and-key to induced fit are plausible, including IDRs that participate in important interactions mediated by fold-upon-binding events [8], or bind without folding [9] Furthermore, the conformational ensemble undergoes p…”
BackgroundInfluentialFonin, A. V., Antifeeva, I. A., Kuznetsova, I. М., Константинович, Т. К., Zaslavsky, B. Y., Kulkarni, P., & Uversky, V. N. (2022) · Essays in Biochemistry · doi:10.1042/ebc20220052 · Cited by 77 · see citing works
Self-citationPositive-unlabelled learning of glycosylation sites in the human proteome
Li, F., Yang, Z., Purcell, A. W., Webb, G. I., Chou, K., Lithgow, T. J., Li, C., & Song, J. (2019) · BMC Bioinformatics · doi:10.1186/s12859-019-2700-1 · Cited by 73 · see citing works
“Such in silico methods for glycosylation site prediction include NetNGlyc [24], NetOGlyc [21], Ensem-bleGly [25], GPP [26], GlycEP [27], ModPred [28], as well as our previously developed tools GlycoMine [29] and GlycoMine struct [30], etc.”
BackgroundMethodThe Pathophysiological Significance of Fibulin-3
Livingstone, I., Uversky, V. N., Furniss, D., & Wiberg, A. (2020) · Biomolecules · doi:10.3390/biom10091294 · Cited by 70 · see citing works
“Disordered proteins or protein regions are often affected by PTMs, such as phosphorylation, glycosylation, methylation, and ubiquitylation [27,28], and serve as major targets for the alternative splicing [29–31].”
BackgroundSelf-citationUnstructural biology of the dengue virus proteins
Meng, F., Badierah, R., Almehdar, H. A., Redwan, E. M. M. M., Kurgan, L., & Uversky, V. N. (2015) · FEBS Journal · doi:10.1111/febs.13349 · Cited by 75 · see citing works
Self-citationLife in Phases: Intra- and Inter- Molecular Phase Transitions in Protein Solutions
Uversky, V., & Finkelstein, A. (2019) · Biomolecules · doi:10.3390/biom9120842 · Cited by 54 · see citing works
Self-citationWang, C., Tan, X., Tang, D., Gou, Y., Han, C., Ning, W., Lin, S., Zhang, W., Chen, M., Peng, D., et al. (2021) · Briefings in Bioinformatics · doi:10.1093/bib/bbab574 · Cited by 71 · see citing works
PTM-Mamba: a PTM-aware protein language model with bidirectional gated Mamba blocks
Peng, F. Z., Wang, C.-T., Chen, T., Schussheim, B., Vincoff, S., & Chatterjee, P. (2025) · Nature Methods · doi:10.1038/s41592-025-02656-9 · Cited by 32 · see citing works
Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)
Klionsky, D. J., Abdelmohsen, K., Abe, A., Abedin, J., Abeliovich, H., Acevedo‐Arozena, A., Adachi, H., Adams, C. M., Adams, P. D., Adeli, K., et al. (2016) · Kölner Universitäts PublikationsServer (Universität zu Köln) · doi:10.5167/uzh-131237 · Cited by 69 · see citing works
Coskuner‐Weber, O., Mirzanli, O., & Uversky, V. N. (2022) · Biophysical Reviews · doi:10.1007/s12551-022-00968-0 · Cited by 69 · see citing works
Self-citationNiklas, K. J., Dunker, A. K., & Yruela, I. (2018) · Journal of Experimental Botany · doi:10.1093/jxb/erx493 · Cited by 67 · see citing works
Self-citationConservation and Divergence of Mediator Structure and Function: Insights from Plants
Dolan, W. L., & Chapple, C. C. S. (2016) · Plant and Cell Physiology · doi:10.1093/pcp/pcw176 · Cited by 64 · see citing works
Co-occurring protein phosphorylation are functionally associated
Li, Y., Zhou, X., Zhai, Z., & Li, T. (2017) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1005502 · Cited by 60 · see citing works
Mutli-Features Prediction of Protein Translational Modification Sites
Bao, W., Yuan, C., Zhang, Y., Han, K., Nandi, A. K., Honig, B. H., & Huang, D.-S. (2017) · IEEE Transactions on Computational Biology and Bioinformatics · doi:10.1109/tcbb.2017.2752703 · Cited by 59 · see citing works
“[35], [36], [37].”
Intrinsic disorder in proteins involved in amyotrophic lateral sclerosis
Santamaria, N., Alhothali, M., Alfonso, M. B. H., Breydo, L., & Uversky, V. N. (2016) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-016-2416-6 · Cited by 60 · see citing works
“Disordered proteins or protein regions are often affected by post translational modifications, such as phosphorylation, glycosylation, methylation, and ubiquitination [24, 25], and serve as major targets for the alternative splicing [26–28].”
BackgroundSelf-citationIntrinsically disordered proteins in the nucleus of human cells
Frege, T., & Uversky, V. N. (2015) · Biochemistry and Biophysics Reports · doi:10.1016/j.bbrep.2015.03.003 · Cited by 58 · see citing works
“Our current work provides additional support to this idea and shows that many subnuclear organelles in human cells are enriched in IDPs and hybrid proteins possessing ordered and disordered domains and that human nuclear proteins are very promiscuous binders possessing both large quantities of potential disorder-based…”
BackgroundInfluentialSelf-citationAndjelković, U., & Josić, D. (2018) · Trends in Food Science & Technology · doi:10.1016/j.tifs.2018.04.008 · Cited by 58 · see citing works
The intrinsic disorder alphabet. III. Dual personality of serine
Uversky, V. N. (2015) · Intrinsically Disordered Proteins · doi:10.1080/21690707.2015.1027032 · Cited by 56 · see citing works
“This conclusion is supported by the resent statistical association study which clearly showed that although many PTM sites were systematically found within the disordered regions, target sites modified by more than one type of PTM showed even stronger preferences toward disordered regions than their single-PTM counter…”
BackgroundResultSelf-citationThe solvent side of proteinaceous membrane-less organelles in light of aqueous two-phase systems
Zaslavsky, B. Y., Ferreira, L. A., Darling, A. L., & Uversky, V. N. (2018) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2018.06.030 · Cited by 55 · see citing works
Self-citationDrug design targeting active posttranslational modification protein isoforms
Meng, F., Liang, Z. T., Zhao, K., & Luo, C. (2020) · Medicinal Research Reviews · doi:10.1002/med.21774 · Cited by 56 · see citing works
“Generally, PTMs preferred sites can be categorized into three major groups: well‐defined secondary structures; intrinsically disordered regions, where the microstate cannot be described by a single dominant one and PPI interfaces.(141) The region for specific molecular recognition is denoted as specificity determinant…”
BackgroundInfluentialZhang, M., Huang, C., Wang, Z., Lv, H., & Li, X. (2020) · BMC Molecular and Cell Biology · doi:10.1186/s12860-020-00252-7 · Cited by 55 · see citing works
Intrinsic disorder is an essential characteristic of components in the conserved circadian circuit
Pelham, J. F., Dunlap, J., & Hurley, J. (2020) · Cell Communication and Signaling · doi:10.1186/s12964-020-00658-y · Cited by 55 · see citing works
Function and dynamics of the intrinsically disordered carboxyl terminus of β2 adrenergic receptor
Heng, J., Hu, Y., Pérez‐Hernández, G., Inoue, A., Zhao, J., Ma, X., Sun, X., Kawakami, K., Ikuta, T., Ding, J., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-37233-1 · Cited by 50 · see citing works
A Dimerization Function in the Intrinsically Disordered N-Terminal Region of Src
Spassov, D. S., Ruiz-Sáenz, A., Piple, A. S., & Moasser, M. M. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.09.035 · Cited by 54 · see citing works
“Indeed, post-translational modifications of the proteome are biased toward IDRs, including phosphorylation, glycosylation, hydroxylation, acetylation, sulfation, ADP ribosylation, SUMOylation, and ubiquitination (Iakoucheva et al., 2004; Pejaver et al., 2014).”
BackgroundGuharoy, M., Bhowmick, P., & Tompa, P. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.r115.692665 · Cited by 53 · see citing works
“Structural disorder facilitates deposition of PTMs, and it can also be argued that multiple modifications within a restricted region would benefit from the structural plasticity/malleability offered by disordered segments (76).”
BackgroundAlghamdi, M., Ghamdi, K. A. A., Khan, R. H., Uversky, V. N., & Redwan, E. M. M. M. (2019) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-019-03237-8 · Cited by 52 · see citing works
Self-citationAn, J., Zhang, X., Li, H., Wang, D., You, C., & Han, Y. (2023) · New Phytologist · doi:10.1111/nph.18997 · Cited by 50 · see citing works
Stetz, G., Tse, A., & Verkhivker, G. M. (2018) · Scientific Reports · doi:10.1038/s41598-018-25329-4 · Cited by 50 · see citing works
Regulation of Lignin Biosynthesis by Post-translational Protein Modifications
Sulis, D. B., & Wang, J. P. (2020) · Frontiers in Plant Science · doi:10.3389/fpls.2020.00914 · Cited by 50 · see citing works
“PTMs are found in diverse classes of proteins, highlighting the regulatory interplay among PTMs as a common strategy to regulate protein functions (Yang, 2005; Nussinov et al., 2012; Lothrop et al., 2013; Pejaver et al., 2014).”
BackgroundGupta, M. N., & Uversky, V. N. (2024) · Protein Science · doi:10.1002/pro.4968 · Cited by 50 · see citing works
“IDRs, with greater accessibility to the modifying enzymes (and the necessary chemical entities), frequently are the sites of PTMs (Darling & Uversky, 2018; Iakoucheva et al., 2004; Pejaver et al., 2014; Uversky, 2013c; Xie, Vucetic, Iakoucheva, Oldfield, Dunker, Uversky, & Obradovic, 2007).”
BackgroundSelf-citationGoretzki, B., Guhl, C., Tebbe, F., Harder, J.-M., & Hellmich, U. A. (2021) · Journal of Molecular Biology · doi:10.1016/j.jmb.2021.166931 · Cited by 48 · see citing works
Sharma, E., Bhatnagar, A., Bhaskar, A., Majee, S. M., Kieffer, M., Kepinski, S., Khurana, P., & Khurana, J. P. (2022) · Plant Cell & Environment · doi:10.1111/pce.14496 · Cited by 47 · see citing works
Introduction to intrinsically disordered proteins and regions
Oldfield, C. J., Uversky, V. N., Dunker, A. K., & Kurgan, L. (2019) · Elsevier eBooks · doi:10.1016/b978-0-12-816348-1.00001-6 · Cited by 47 · see citing works
Self-citationAnalyzing IDPs in Interactomes
Uversky, V. N. (2020) · Methods in molecular biology · doi:10.1007/978-1-0716-0524-0_46 · Cited by 47 · see citing works
Self-citationA Comprehensive Survey of the Roles of Highly Disordered Proteins in Type 2 Diabetes
Du, Z., & Uversky, V. N. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18102010 · Cited by 46 · see citing works
“On a more general note, the broad involvement of intrinsically disordered proteins (IDPs) and protein regions (IDPRs) in the pathogenesis of several human diseases, such as amyloidosis, cardiovascular disease, cancer, diabetes, and neurodegeneration, was pointed out, and a D2 (disorder in disorders) concept was introd…”
BackgroundInfluentialSelf-citationPost‐translationally‐modified structures in the autophagy machinery: an integrative perspective
Popelka, H., & Klionsky, D. J. (2015) · FEBS Journal · doi:10.1111/febs.13356 · Cited by 45 · see citing works
Erady, C., Boxall, A. R., Puntambekar, S. S., Jagannathan, N. S., Chauhan, R., Chong, D. H., Meena, N. K., Kulkarni, A., Kasabe, B., Bhayankaram, K. P., et al. (2021) · npj Genomic Medicine · doi:10.1038/s41525-020-00167-4 · Cited by 45 · see citing works
Entropy and Information within Intrinsically Disordered Protein Regions
Pritišanac, I., Vernon, R. M., Moses, A. M., & Forman-Kay, J. D. (2019) · Entropy · doi:10.3390/e21070662 · Cited by 44 · see citing works
An atlas of posttranslational modifications on RNA binding proteins
England, W., Wang, J., Chen, S., Baldi, P., Flynn, R. A., & Spitale, R. C. (2022) · Nucleic Acids Research · doi:10.1093/nar/gkac243 · Cited by 43 · see citing works
“PTMs are known to regulate protein structure, localization, decay and signaling activities (14,15).”
Structure and function of yeast Atg20, a sorting nexin that facilitates autophagy induction
Popelka, H., Damasio, A., Hinshaw, J. E., Klionsky, D. J., & Ragusa, M. J. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1708367114 · Cited by 41 · see citing works
“Protein function, stability, or folding efficiency can be affected by posttranslational modifications (PTMs) (29).”
BackgroundInfluentialCirculating extracellular vesicles and rheumatoid arthritis: a proteomic analysis
Alghamdi, M., Alamry, S. A., Bahlas, S. M., Uversky, V. N., & Redwan, E. M. M. M. (2021) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-021-04020-4 · Cited by 39 · see citing works
“It is worth noting that in comparison to exosomes, MVs are markedly enriched in glycoproteins and phosphoproteins, i.e., proteins that underwent posttranslational modifications (PTMs), such as glycosylation and phosphorylation [124, 125].”
BackgroundInfluentialSelf-citationUversky, V. N. (2019) · Molecules · doi:10.3390/molecules24183265 · Cited by 39 · see citing works
“Also, IDPs/IDPRs are known to be commonly subjected to various post-translational modifications (PTMs) [112,113].”
BackgroundSelf-citationChaudhari, M., Thapa, N., Roy, K., Newman, R. H., Saigo, H., & C., D. B. K. (2020) · Molecular Omics · doi:10.1039/d0mo00025f · Cited by 39 · see citing works
Paradoxes and wonders of intrinsic disorder: Stability of instability
Uversky, V. N. (2017) · Intrinsically Disordered Proteins · doi:10.1080/21690707.2017.1327757 · Cited by 39 · see citing works
“protection, controlled cell death, and cellular homeostasis.(1-7,10-41) Several recent studies (mostly of compu-”
BackgroundSelf-citation
- Authors
- Pejaver, V., Hsu, W., Xin, F., Dunker, A. K., Uversky, V. N., & Radivojac, P.
- Affiliations
- Indiana University Bloomington (US)
- Indiana University Indianapolis (US)
- General Electric (United States) (US)
- Russian Academy of Sciences (RU)
- Department of Computer Science and Informatics Indiana University Bloomington Indiana 47405
- Venue
- Protein Science
- Publisher
- Wiley
- Published
- 2014-06-11
- Volume
- 23
- Issue
- 8
- Pages
- 1077-1093
- ISSN
- 0961-8368 (ISSN-L)
- 1469-896X
- PMC
- PMC4116656
- OpenAlex
- W2124052876
- Cited by
- 349
- References
- 98
- Citations by year
- 2026: 10 · 2025: 18 · 2024: 24 · 2023: 20 · 2022: 35 · 2021: 43 · 2020: 35 · 2019: 34 · 2018: 34 · 2017: 32 · 2016: 37 · 2015: 21 · 2014: 5
- FWCI
- 12.98
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Protein Science (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Digital Commons - University of South Florida (University of South Florida) (submittedVersion)
- IUScholarWorks (Indiana University) (submittedVersion)
- PMC
- Funders
- National Science Foundation (DBI-0644017)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Machine Learning in Bioinformatics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- post-translational modification, PTM crosstalk, PTM site prediction, intrinsically disordered regions, molecular recognition features, protein-protein interaction, transcriptional regulation, developmental processes, eukaryotic proteins
- MeSH terms
- Models, Molecular, Protein Conformation, Protein Processing, Post-Translational, Proteins
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