Intrinsic protein disorder in histone lysine methylation

Lázár, Tamás; Schád, Éva; Szabó, Beáta; Horváth, Tamás; Mészáros, Attila; Tompa, Péter; Tantos, Ágnes

doi:10.1186/s13062-016-0129-2

Cited by 20 publications

(16 citation statements)

References 55 publications

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“…The interactions between DFS70/LEDGF and its partners at the IBD appear to be stabilized by intrinsically disordered regions (IDRs). For instance, a disordered IBD-binding short linear motif (IBM) was recently identified in several DFS70/LEDGF interacting partners, with their affinity for IBD binding regulated by phosphorylation of the IBM [45,60,61]. DFS70/LEDGF itself is also an IDR protein, having only two domains that can form stable 3D structures, the PWWP and IBD, which are separated by an IDR (residues 100-345) that lacks welldefined tertiary structure (Fig.…”

Section: Hsp27mentioning

confidence: 99%

Twenty years of research on the DFS70/LEDGF autoantibody-autoantigen system: many lessons learned but still many questions

Ortiz-Hernández

Sanchez-Hernández

Casiano

2020

Autoimmun Highlights

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The discovery and initial characterization 20 years ago of antinuclear autoantibodies (ANAs) presenting a dense fine speckled (DFS) nuclear pattern with strong staining of mitotic chromosomes, detected by indirect immunofluorescence assay in HEp-2 cells (HEp-2 IIFA test), has transformed our view on ANAs. Traditionally, ANAs have been considered as reporters of abnormal immunological events associated with the onset and progression of systemic autoimmune rheumatic diseases (SARD), also called ANA-associated rheumatic diseases (AARD), as well as clinical biomarkers for the differential diagnosis of these diseases. However, based on our current knowledge, it is not apparent that autoantibodies presenting the DFS IIF pattern fall into these categories. These antibodies invariably target a chromatin-associated protein designated as dense fine speckled protein of 70 kD (DFS70), also known as lens epitheliumderived growth factor protein of 75 kD (LEDGF/p75) and PC4 and SFRS1 Interacting protein 1 (PSIP1). This multi-functional protein, hereafter referred to as DFS70/LEDGF, plays important roles in the formation of transcription complexes in active chromatin, transcriptional activation of specific genes, regulation of mRNA splicing, DNA repair, and cellular survival against stress. Due to its multiple functions, it has emerged as a key protein contributing to several human pathologies, including acquired immunodeficiency syndrome (AIDS), leukemia, cancer, ocular diseases, and Rett syndrome. Unlike other ANAs, "monospecific" anti-DFS70/LEDGF autoantibodies (only detectable ANA in serum) are not associated with SARD and have been detected in healthy individuals and some patients with non-SARD inflammatory conditions. These observations have led to the hypotheses that these antibodies could be considered as negative biomarkers of SARD and might even play a protective or beneficial role. In spite of 20 years of research on this autoantibody-autoantigen system, its biological and clinical significance still remains enigmatic. Here we review the current state of knowledge of this system, focusing on the lessons learned and posing emerging questions that await further scrutiny as we continue our quest to unravel its significance and potential clinical and therapeutic utility.

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Section: Hsp27mentioning

confidence: 99%

Twenty years of research on the DFS70/LEDGF autoantibody-autoantigen system: many lessons learned but still many questions

Ortiz-Hernández

Sanchez-Hernández

Casiano

2020

Autoimmun Highlights

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“…In a previous work [ 26 ] we suggested that the disordered regions of HKMTs may harbor so far unrecognized interaction sites, adding more layers of the regulation of their activity. Based on the observation that many lncRNAs are involved in processes governed by HKMTs, we hypothesized that lncRNA binding might be one of the functions of these regions.…”

Section: Introductionmentioning

confidence: 99%

Disordered Regions of Mixed Lineage Leukemia 4 (MLL4) Protein Are Capable of RNA Binding

Szabó

Murvai

Abukhairan

et al. 2018

IJMS

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Long non-coding RNAs (lncRNAs) are emerging as important regulators of cellular processes and are extensively involved in the development of different cancers; including leukemias. As one of the accepted methods of lncRNA function is affecting chromatin structure; lncRNA binding has been shown for different chromatin modifiers. Histone lysine methyltransferases (HKMTs) are also subject of lncRNA regulation as demonstrated for example in the case of Polycomb Repressive Complex 2 (PRC2). Mixed Lineage Leukemia (MLL) proteins that catalyze the methylation of H3K4 have been implicated in several different cancers; yet many details of their regulation and targeting remain elusive. In this work we explored the RNA binding capability of two; so far uncharacterized regions of MLL4; with the aim of shedding light to the existence of possible regulatory lncRNA interactions of the protein. We demonstrated that both regions; one that contains a predicted RNA binding sequence and one that does not; are capable of binding to different RNA constructs in vitro. To our knowledge, these findings are the first to indicate that an MLL protein itself is capable of lncRNA binding.

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“…Structural disorder was predicted for all the associated proteins by IUPred [ 23 , 24 ], which is a conservative disorder prediction method showing good correspondence [ 25 ] with the consensus disorder patterns of MobiDB [ 26 ]. The average fraction of disordered residues in the obtained proteomes ranged between 1 and 12 %, with a median of 3.7 % that is extremely low compared to other organisms [ 16 ].…”

Section: Resultsmentioning

confidence: 99%

Essential functions linked with structural disorder in organisms of minimal genome

Pancsa

Tompa

2016

Biol Direct

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Intrinsically disordered regions (IDRs) of proteins fulfill important regulatory roles in most organisms. However, the proteins of certain endosymbiont and intracellular pathogenic bacteria with extremely reduced genomes contain disproportionately small amounts of IDRs, consisting almost entirely of folded domains. As their genomes co-evolving with their hosts have been reduced in unrelated lineages, the proteomes of these bacteria represent independently evolved minimal protein sets. We systematically analyzed structural disorder in a representative set of such minimal organisms to see which types of functionally relevant longer IDRs are invariably retained in them. We found that a few characteristic functions are consistently linked with conformational disorder: ribosomal proteins, key components of the protein production machinery, a central coordinator of DNA metabolism and certain housekeeping chaperones seem to strictly rely on structural disorder even in genome-reduced organisms. We propose that these functions correspond to the most essential and probably also the most ancient ones fulfilled by structural disorder in cellular organisms.ReviewersThis article was reviewed by Michael Gromiha, Zoltan Gaspari and Sandor Pongor.Electronic supplementary materialThe online version of this article (doi:10.1186/s13062-016-0149-y) contains supplementary material, which is available to authorized users.

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Intrinsic protein disorder in histone lysine methylation

Cited by 20 publications

References 55 publications

Twenty years of research on the DFS70/LEDGF autoantibody-autoantigen system: many lessons learned but still many questions

Twenty years of research on the DFS70/LEDGF autoantibody-autoantigen system: many lessons learned but still many questions

Disordered Regions of Mixed Lineage Leukemia 4 (MLL4) Protein Are Capable of RNA Binding

Essential functions linked with structural disorder in organisms of minimal genome

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