An Amyloidogenic Sequence at the N-Terminus of the Androgen Receptor Impacts Polyglutamine Aggregation

The human androgen receptor (AR) is a ligand inducible transcription factor harboring an amino terminal domain (AR-NTD) hosting the ligand independent activation function. AR-NTD is intrinsically disordered and display aggregation properties conferred by the presence of a poly-glutamine (polyQ) sequence of 22 residues. The length of the polyQ sequence, as well as the presence of adjacent sequence motifs modulate this aggregation property. AR-NTD contains also a conserved sequence motif KELCKAVSVSM that displays an intrinsic property to form amyloid fibrils under mild oxidative conditions of its conserved cysteine residue. As peptide sequences with intrinsic ability to oligomerize are reported to have an impact on the aggregation of polyQ tract, we determined the effect of the KELCKAVSVSM on the polyQ stretch in the context of the AR NTD, using Atomic Force Microscopy (AFM). Here, we present evidence for a crosstalk between the amyloidogenic properties of the KELCKAVSVSM motif and the polyQ stretch at the AR NTD.

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CMD: A Database to Store the Bonding States of Cysteine Motifs with Secondary Structures

Advances in Bioinformatics ◽

10.1155/2012/849830 ◽

2012 ◽

Vol 2012 ◽

pp. 1-5 ◽

Cited By ~ 2

Author(s):

Hamed Bostan ◽

Naomie Salim ◽

Zeti Azura Hussein ◽

Peter Klappa ◽

Mohd Shahir Shamsir

Keyword(s):

Secondary Structure ◽

High Throughput Screening ◽

Laboratory Data ◽

Cysteine Residue ◽

Third Party ◽

Connectivity Pattern ◽

Cysteine Residues ◽

Sequence Motif ◽

Sequence Motifs ◽

Cysteine Motifs

Computational approaches to the disulphide bonding state and its connectivity pattern prediction are based on various descriptors. One descriptor is the amino acid sequence motifs flanking the cysteine residue motifs. Despite the existence of disulphide bonding information in many databases and applications, there is no complete reference and motif query available at the moment. Cysteine motif database (CMD) is the first online resource that stores all cysteine residues, their flanking motifs with their secondary structure, and propensity values assignment derived from the laboratory data. We extracted more than 3 million cysteine motifs from PDB and UniProt data, annotated with secondary structure assignment, propensity value assignment, and frequency of occurrence and coefficiency of their bonding status. Removal of redundancies generated 15875 unique flanking motifs that are always bonded and 41577 unique patterns that are always nonbonded. Queries are based on the protein ID, FASTA sequence, sequence motif, and secondary structure individually or in batch format using the provided APIs that allow remote users to query our database via third party software and/or high throughput screening/querying. The CMD offers extensive information about the bonded, free cysteine residues, and their motifs that allows in-depth characterization of the sequence motif composition.

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Sintokamide A Is a Novel Antagonist of Androgen Receptor That Uniquely Binds Activation Function-1 in Its Amino-terminal Domain

Journal of Biological Chemistry ◽

10.1074/jbc.m116.734475 ◽

2016 ◽

Vol 291 (42) ◽

pp. 22231-22243 ◽

Cited By ~ 22

Author(s):

Carmen A. Banuelos ◽

Iran Tavakoli ◽

Amy H. Tien ◽

Daniel P. Caley ◽

Nasrin R. Mawji ◽

...

Keyword(s):

Androgen Receptor ◽

Activation Function ◽

Amino Terminal ◽

Terminal Domain ◽

Amino Terminal Domain

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Integration of viral transcriptome sequencing with structure and sequence motifs predicts novel regulatory elements in SARS-CoV-2

10.1101/2020.06.24.169144 ◽

2020 ◽

Author(s):

Brian J. Cox

Keyword(s):

Regulatory Elements ◽

Viral Gene ◽

Template Switching ◽

Sequence Motif ◽

Sequence Motifs ◽

Human Pathogens ◽

Sequencing Data ◽

Stem Loop ◽

Conserved Sequence ◽

Splice Junctions

SummaryIn the last twenty years, three separate coronaviruses have left their typical animal hosts and became human pathogens. An area of research interest is coronavirus transcription regulation that uses an RNA-RNA mediated template-switching mechanism. It is not known how different transcriptional stoichiometries of each viral gene are generated. Analysis of SARS-CoV-2 RNA sequencing data from whole RNA transcriptomes identified TRS dependent and independent transcripts. Integration of transcripts and 5’-UTR sequence motifs identified that the pentaloop and the stem-loop 3 were also located upstream of spliced genes. TRS independent transcripts were detected as likely non-polyadenylated. Additionally, a novel conserved sequence motif was discovered at either end of the TRS independent splice junctions. While similar both SARS viruses generated similar TRS independent transcripts they were more abundant in SARS-CoV-2. TRS independent gene regulation requires investigation to determine its relationship to viral pathogenicity.

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PETISCO is a novel protein complex required for 21U RNA biogenesis and embryonic viability

10.1101/463711 ◽

2018 ◽

Cited By ~ 1

Author(s):

Ricardo J. Cordeiro Rodrigues ◽

António Miguel de Jesus Domingues ◽

Svenja Hellmann ◽

Sabrina Dietz ◽

Bruno F. M. de Albuquerque ◽

...

Keyword(s):

Protein Complex ◽

Intrinsically Disordered Proteins ◽

Rna Binding ◽

Disordered Proteins ◽

Sequence Motif ◽

C Elegans ◽

Conserved Sequence ◽

Intrinsically Disordered ◽

Rna Biogenesis ◽

Novel Protein

AbstractPiwi proteins are important for germ cell development in almost all animals studied thus far. These proteins are guided to specific targets, such as transposable elements, by small guide RNAs, often referred to as piRNAs, or 21U RNAs in C. elegans. In this organism, even though genetic screens have uncovered a number of potential 21U RNA biogenesis factors, little is known about how these factors interact or what they do. Based on the previously identified 21U biogenesis factor PID-1, we here define a novel protein complex, PETISCO, that is required for 21U RNA biogenesis. PETISCO contains both potential 5’-cap and 5’-phosphate RNA binding domains, suggesting involvement in 5’ end processing. We define the interaction architecture of PETISCO and reveal a second function for PETISCO in embryonic development. This essential function of PETISCO is not mediated by PID-1, but by TOST-1. Vice versa, TOST-1 is not involved in 21U RNA biogenesis. Both PID-1 and TOST-1 are small, intrinsically disordered proteins that interact directly with the PETISCO protein ERH-2 (enhancer of rudimentary homolog 2) using a conserved sequence motif. Finally, our data suggest an important role for TOST-1:PETISCO in SL1 homeostasis in the early embryo. Our work describes the first molecular platform for 21U RNA production in C. elegans, and strengthens the view that 21U RNA biogenesis is built upon a much more widely used, snRNA-related pathway.

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MEF2B is a potent transactivator expressed in early myogenic lineages.

Molecular and Cellular Biology ◽

10.1128/mcb.16.7.3814 ◽

1996 ◽

Vol 16 (7) ◽

pp. 3814-3824 ◽

Cited By ~ 80

Author(s):

J D Molkentin ◽

A B Firulli ◽

B L Black ◽

J F Martin ◽

C M Hustad ◽

...

Keyword(s):

Dna Binding ◽

Dna Sequence ◽

Transcriptional Activation ◽

Chromosome 8 ◽

The Other ◽

Carboxyl Terminus ◽

Sequence Motifs ◽

Ancestral Gene ◽

Conserved Sequence ◽

Amino Terminal

There are four members of the myocyte enhancer binding factor 2 (MEF2) family of transcription factors, MEF2A, -B, -C, and -D, that have homology within an amino-terminal MADS box and an adjacent MEF2 domain that together mediate dimerization and DNA binding. MEF2A, -C, and -D have previously been shown to bind an A/T-rich DNA sequence in the control regions of numerous muscle-specific genes, whereas MEF2B was reported to be unable to bind this sequence unless the carboxyl terminus was deleted. To further define the functions of MEF2B, we analyzed its DNA binding and transcriptional activities. In contrast to previous studies, our results show that MEF2B binds the same DNA sequence as other members of the MEF2 family and acts as a strong transactivator through that sequence. Transcriptional activation by MEF2B is dependent on the carboxyl terminus, which contains two conserved sequence motifs found in all vertebrate MEF2 factors. During mouse embryogenesis, MEF2B transcripts are expressed in the developing cardiac and skeletal muscle lineages in a temporospatial pattern distinct from but overlapping with those of the other Mef2 genes. The mouse Mef2b gene maps to chromosome 8 and is unlinked to other Mef2 genes; its intron-exon organization is similar to that of the other vertebrate Mef2 genes and the single Drosophila Mef2 gene, consistent with the notion that these different Mef2 genes evolved from a common ancestral gene.

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Identification of new skeletogenic genes of the sea urchin embryo by use of conserved sequence motifs among the SM50 gene family

Zygote ◽

10.1017/s0967199400130412 ◽

1999 ◽

Vol 8 (S1) ◽

pp. S74-S74

Author(s):

Youn-Ho Lee ◽

Jaeil Kwak ◽

Roy J. Britten ◽

Eric H. Davidson

Keyword(s):

Gene Family ◽

Sea Urchin ◽

Matrix Protein ◽

Early Embryo ◽

Sequence Motifs ◽

Specific Expression ◽

Conserved Sequence ◽

Amino Terminal ◽

Cellular Processes ◽

Conserved Sequence Motifs

Spicule formation in the sea urchin is one of the conspicuous cellular processes occurring in early embryo-genesis, in which stereotyped spicules form through deposition of minerals onto the spicule matrix protein scaffold. This process requires many genes to be functional: the spicule matrix alone needs more than 50 different genes. Until now, however, only a few skeletogenic genes have been known. Recently SM37, a new putative spicule matrix protein gene, was cloned and found to be linked to SM50 (Lee et al., 1999). The structure of the new gene raised the possibility of the presence of a gene family involved in skeletogenesis which consists of SM50, SM37 and LSM34 (a homologue of SM50) (Benson et al., 1987; Livingston et al., 1991). Characteristics of the gene family include: (1) skeletongenic mesenchyme-specific expression, (2) onset of gene expression as early as the mesenchyme blastula, (3) presence of glycine, proline and glutamine-rich repeats in the middle of the proteins. Another feature of the family is the presence of conserved sequence motifs at both the amino-terminal and carboxyl-terminal regions of the proteins – SCYR(A/Y)F and PNPXXXRPRM(L/Y)QE, respectively – which we speculate play a role in protein guidance.

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Cellular Chaperone Function of Intrinsically Disordered Dehydrin ERD14

International Journal of Molecular Sciences ◽

10.3390/ijms22126190 ◽

2021 ◽

Vol 22 (12) ◽

pp. 6190

Author(s):

Nikoletta Murvai ◽

Lajos Kalmar ◽

Beata Szabo ◽

Eva Schad ◽

András Micsonai ◽

...

Keyword(s):

Intrinsically Disordered Proteins ◽

Stress Protein ◽

Early Response ◽

Disordered Proteins ◽

Proper Function ◽

Sequence Motifs ◽

Protective Function ◽

Cellular Protection ◽

Conserved Sequence ◽

Intrinsically Disordered

Disordered plant chaperones play key roles in helping plants survive in harsh conditions, and they are indispensable for seeds to remain viable. Aside from well-known and thoroughly characterized globular chaperone proteins, there are a number of intrinsically disordered proteins (IDPs) that can also serve as highly effective protecting agents in the cells. One of the largest groups of disordered chaperones is the group of dehydrins, proteins that are expressed at high levels under different abiotic stress conditions, such as drought, high temperature, or osmotic stress. Dehydrins are characterized by the presence of different conserved sequence motifs that also serve as the basis for their categorization. Despite their accepted importance, the exact role and relevance of the conserved regions have not yet been formally addressed. Here, we explored the involvement of each conserved segment in the protective function of the intrinsically disordered stress protein (IDSP) A. thaliana’s Early Response to Dehydration (ERD14). We show that segments that are directly involved in partner binding, and others that are not, are equally necessary for proper function and that cellular protection emerges from the balanced interplay of different regions of ERD14.

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The Androgen Receptor Amino-Terminal Domain Plays a Key Role in p160 Coactivator-Stimulated Gene Transcription

Molecular and Cellular Biology ◽

10.1128/mcb.19.9.6085 ◽

1999 ◽

Vol 19 (9) ◽

pp. 6085-6097 ◽

Cited By ~ 190

Author(s):

Philippe Alen ◽

Frank Claessens ◽

Guido Verhoeven ◽

Wilfried Rombauts ◽

Ben Peeters

Keyword(s):

Androgen Receptor ◽

Mammalian Cells ◽

Transcriptional Activity ◽

Activation Function ◽

Binding Domain ◽

Functional Interaction ◽

Full Size ◽

Amino Terminal ◽

Terminal Domain ◽

Amino Terminal Domain

ABSTRACT Steroid receptors are conditional transcription factors that, upon binding to their response elements, regulate the expression of target genes via direct protein interactions with transcriptional coactivators. We have analyzed the functional interactions between the androgen receptor (AR) and 160-kDa nuclear receptor coactivators. Upon overexpression in mammalian cells, these coactivators enhance the transcriptional activity of both the amino-terminal domain (NTD) and the ligand-binding domain (LBD) of the AR. The coactivator activity for the LBD is strictly ligand-controlled and depends on the nature of the DNA-binding domain to which it is fused. We demonstrate that the NTD physically interacts with coactivators and with the LBD and that this interaction, like the functional interaction between the LBD and p160 coactivators, relies on the activation function 2 (AF2) core domain. The mutation of a highly conserved lysine residue in the predicted helix 3 of the LBD (K720A), however, blunts the functional interaction with coactivators but not with the NTD. Moreover, this mutation does not affect the transcriptional activity of the full-size AR. A mutation in the NTD of activation function AF1a (I182A/L183A), which dramatically impairs the activity of the AR, has no effect on the intrinsic transcriptional activity of the NTD but interferes with the cooperation between the NTD and the LBD. Finally, p160 proteins in which the three LXXLL motifs are mutated retain most of their coactivator activity for the full-size AR, although they are no longer functional for the isolated LBD. Together, these data suggest that in the native AR the efficient recruitment of coactivators requires a functional association of the NTD with the LBD and that the binding of coactivators occurs primarily through the NTD.

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Senescence-associated Barley NAC (NAM, ATAF1,2, CUC) Transcription Factor Interacts with Radical-induced Cell Death 1 through a Disordered Regulatory Domain

Journal of Biological Chemistry ◽

10.1074/jbc.m111.247221 ◽

2011 ◽

Vol 286 (41) ◽

pp. 35418-35429 ◽

Cited By ~ 56

Author(s):

Trine Kjaersgaard ◽

Michael K. Jensen ◽

Michael W. Christiansen ◽

Per Gregersen ◽

Birthe B. Kragelund ◽

...

Keyword(s):

Cell Death ◽

Regulatory Protein ◽

Intrinsic Disorder ◽

Target Sequence ◽

Sequence Motifs ◽

Conserved Sequence ◽

Intrinsically Disordered ◽

Age Related ◽

Terminal Domains

Senescence in plants involves massive nutrient relocation and age-related cell death. Characterization of the molecular components, such as transcription factors (TFs), involved in these processes is required to understand senescence. We found that HvNAC005 and HvNAC013 of the plant-specific NAC (NAM, ATAF1,2, CUC) TF family are up-regulated during senescence in barley (Hordeum vulgare). Both HvNAC005 and HvNAC013 bound the conserved NAC DNA target sequence. Computational and biophysical analyses showed that both proteins are intrinsically disordered in their large C-terminal domains, which are transcription regulatory domains (TRDs) in many NAC TFs. Using motif searches and interaction studies in yeast we identified an evolutionarily conserved sequence, the LP motif, in the TRD of HvNAC013. This motif was sufficient for transcriptional activity. In contrast, HvNAC005 did not function as a transcriptional activator suggesting that an involvement of HvNAC013 and HvNAC005 in senescence will be different. HvNAC013 interacted with barley radical-induced cell death 1 (RCD1) via the very C-terminal part of its TRD, outside of the region containing the LP motif. No significant secondary structure was induced in the HvNAC013 TRD upon interaction with RCD1. RCD1 also interacted with regions dominated by intrinsic disorder in TFs of the MYB and basic helix-loop-helix families. We propose that RCD1 is a regulatory protein capable of interacting with many different TFs by exploiting their intrinsic disorder. In addition, we present the first structural characterization of NAC C-terminal domains and relate intrinsic disorder and sequence motifs to activity and protein-protein interactions.

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Analysis of mutations in the sqt-1 and rol-6 collagen genes of Caenorhabditis elegans.

Genetics ◽

10.1093/genetics/135.4.1035 ◽

1993 ◽

Vol 135 (4) ◽

pp. 1035-1045 ◽

Cited By ~ 3

Author(s):

J M Kramer ◽

J J Johnson

Keyword(s):

Caenorhabditis Elegans ◽

Nonsense Mutation ◽

Cysteine Residue ◽

Nonsense Mutations ◽

C Elegans ◽

Conserved Sequence ◽

Amino Terminal ◽

Carboxy Terminal ◽

Collagen Genes ◽

Cuticle Collagens

Abstract Different mutations in the sqt-1 and rol-6 collagen genes of Caenorhabditis elegans can cause diverse changes in body morphology and display different genetic attributes. We have determined the nucleotide alterations in 15 mutant alleles of these genes. Three mutations in sqt-1 and one in rol-6 that cause dominant right-handed helical twisting (RRol) of animals are arginine to cysteine replacements. These mutations are all within a short conserved sequence, on the amino terminal side of the Gly-X-Y repeats, that is found in all C. elegans cuticle collagens. A recessive RRol mutation of rol-6 is a replacement of one of the same conserved arginines by histidine. In contrast, three sqt-1 mutations that cause recessive left-handed helical twisting (LRol) are replacements of a conserved carboxy-terminal cysteine residue with either tyrosine or serine. These results suggest that disulfide bonding is important in collagen organization and that a deficit or surplus of disulfides may cause cuticle alterations of opposite handedness. In contrast to other collagens, glycine replacement mutations in the Gly-X-Y repeats of sqt-1 cause very mild phenotypes. Nonsense mutations of both sqt-1 and rol-6 cause nearly, but not totally, wild-type phenotypes. A nonsense mutation in sqt-1 suppresses the phenotype of rol-6 RRol mutations, suggesting that rol-6 collagen function is dependent on the presence of sqt-1 collagen. Mutations of sqt-1 are not suppressed by a rol-6 nonsense mutation, however, indicating that sqt-1 collagen can function independently of rol-6.

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