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Article ; Online: Advances in Nucleotide Repeat Expansion Diseases

Ana S. Figueiredo / Joana R. Loureiro / Sandra Macedo-Ribeiro / Isabel Silveira

Cells, Vol 12, Iss 826, p

Transcription Gets in Phase

2023 Volume 826

Abstract: Unstable DNA repeat expansions and insertions have been found to cause more than 50 neurodevelopmental, neurodegenerative, and neuromuscular disorders. One of the main hallmarks of repeat expansion diseases is the formation of abnormal RNA or protein ... ...

Abstract	Unstable DNA repeat expansions and insertions have been found to cause more than 50 neurodevelopmental, neurodegenerative, and neuromuscular disorders. One of the main hallmarks of repeat expansion diseases is the formation of abnormal RNA or protein aggregates in the neuronal cells of affected individuals. Recent evidence indicates that alterations of the dynamic or material properties of biomolecular condensates assembled by liquid/liquid phase separation are critical for the formation of these aggregates. This is a thermodynamically-driven and reversible local phenomenon that condenses macromolecules into liquid-like compartments responsible for compartmentalizing molecules required for vital cellular processes. Disease-associated repeat expansions modulate the phase separation properties of RNAs and proteins, interfering with the composition and/or the material properties of biomolecular condensates and resulting in the formation of abnormal aggregates. Since several repeat expansions have arisen in genes encoding crucial players in transcription, this raises the hypothesis that wide gene expression dysregulation is common to multiple repeat expansion diseases. This review will cover the impact of these mutations in the formation of aberrant aggregates and how they modify gene transcription.
Keywords	liquid/liquid phase separation ; RNA-binding protein ; RNA/protein aggregates ; polyalanine ; polyglutamine ; NIID ; Biology (General) ; QH301-705.5
Subject code	612
Language	English
Publishing date	2023-03-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Trinucleotide Repeats

SandraMacedo-Ribeiro

Frontiers in Neurology, Vol

A structural perspective

2013 Volume 4

Abstract: Trinucleotide repeat (TNR) expansions are present in a wide range of genes involved in several neurological disorders, being directly involved in the molecular mechanisms underlying pathogenesis through modulation of gene expression and/or the function ... ...

Abstract	Trinucleotide repeat (TNR) expansions are present in a wide range of genes involved in several neurological disorders, being directly involved in the molecular mechanisms underlying pathogenesis through modulation of gene expression and/or the function of the RNA or protein it encodes. Structural and functional information on the role of TNR sequences in RNA and protein is crucial to understand the effect of TNR expansions in neurodegeneration. Therefore, this review intends to provide to the reader a structural and functional view of TNR and encoded homopeptide expansions, with a particular emphasis on polyQ expansions and its role at inducing the self-assembly, aggregation and functional alterations of the carrier protein, which culminates in neuronal toxicity and cell death. Detail will be given to the Machado Joseph Disease (MJD)-causative and polyQ-containing protein, ataxin-3, providing clues for the impact of polyQ expansion and its flanking regions in the modulation of ataxin-3 molecular interactions, function and aggregation.
Keywords	Amyloid ; protein aggregation ; Protein complexes ; protein structure ; microsatellites ; Amino acid repeats ; Neurology. Diseases of the nervous system ; RC346-429 ; Neurosciences. Biological psychiatry. Neuropsychiatry ; RC321-571 ; Internal medicine ; RC31-1245 ; Medicine ; R
Subject code	612
Language	English
Publishing date	2013-06-01T00:00:00Z
Publisher	Frontiers Media S.A.
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: CARs-DB

Carlos Pintado-Grima / Oriol Bárcenas / Zoe Manglano-Artuñedo / Rita Vilaça / Sandra Macedo-Ribeiro / Irantzu Pallarès / Jaime Santos / Salvador Ventura

Frontiers in Molecular Biosciences, Vol

A Database of Cryptic Amyloidogenic Regions in Intrinsically Disordered Proteins

2022 Volume 9

Abstract: Proteome-wide analyses suggest that most globular proteins contain at least one amyloidogenic region, whereas these aggregation-prone segments are thought to be underrepresented in intrinsically disordered proteins (IDPs). In recent work, we reported ... ...

Abstract	Proteome-wide analyses suggest that most globular proteins contain at least one amyloidogenic region, whereas these aggregation-prone segments are thought to be underrepresented in intrinsically disordered proteins (IDPs). In recent work, we reported that intrinsically disordered regions (IDRs) indeed sustain a significant amyloid load in the form of cryptic amyloidogenic regions (CARs). CARs are widespread in IDRs, but they are necessarily exposed to solvent, and thus they should be more polar and have a milder aggregation potential than conventional amyloid regions protected inside globular proteins. CARs are connected with IDPs function and, in particular, with the establishment of protein-protein interactions through their IDRs. However, their presence also appears associated with pathologies like cancer or Alzheimer’s disease. Given the relevance of CARs for both IDPs function and malfunction, we developed CARs-DB, a database containing precomputed predictions for all CARs present in the IDPs deposited in the DisProt database. This web tool allows for the fast and comprehensive exploration of previously unnoticed amyloidogenic regions embedded within IDRs sequences and might turn helpful in identifying disordered interacting regions. It contains >8,900 unique CARs identified in a total of 1711 IDRs. CARs-DB is freely available for users and can be accessed at http://carsdb.ppmclab.com. To validate CARs-DB, we demonstrate that two previously undescribed CARs selected from the database display full amyloidogenic potential. Overall, CARs-DB allows easy access to a previously unexplored amyloid sequence space.
Keywords	amyloid ; intrinsically disordered proteins ; database ; disease ; protein-protein interactions ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2022-05-01T00:00:00Z
Publisher	Frontiers Media S.A.
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: A Robust Assay to Monitor Ataxin-3 Amyloid Fibril Assembly

Francisco Figueiredo / Mónica Lopes-Marques / Bruno Almeida / Nena Matscheko / Pedro M. Martins / Alexandra Silva / Sandra Macedo-Ribeiro

Cells, Vol 11, Iss 1969, p

2022 Volume 1969

Abstract: Spinocerebellar ataxia type 3 (SCA3) is caused by the expansion of a glutamine repeat in the protein ataxin-3, which is deposited as intracellular aggregates in affected brain regions. Despite the controversial role of ataxin-3 amyloid structures in SCA3 ...

Abstract	Spinocerebellar ataxia type 3 (SCA3) is caused by the expansion of a glutamine repeat in the protein ataxin-3, which is deposited as intracellular aggregates in affected brain regions. Despite the controversial role of ataxin-3 amyloid structures in SCA3 pathology, the identification of molecules with the capacity to prevent aberrant self-assembly and stabilize functional conformation(s) of ataxin-3 is a key to the development of therapeutic solutions. Amyloid-specific kinetic assays are routinely used to measure rates of protein self-assembly in vitro and are employed during screening for fibrillation inhibitors. The high tendency of ataxin-3 to assemble into oligomeric structures implies that minor changes in experimental conditions can modify ataxin-3 amyloid assembly kinetics. Here, we determine the self-association rates of ataxin-3 and present a detailed study of the aggregation of normal and pathogenic ataxin-3, highlighting the experimental conditions that should be considered when implementing and validating ataxin-3 amyloid progress curves in different settings and in the presence of ataxin-3 interactors. This assay provides a unique and robust platform to screen for modulators of the first steps of ataxin-3 aggregation—a starting point for further studies with cell and animal models of SCA3.
Keywords	thioflavin-T ; polyglutamine expansion ; reproducibility ; ubiquitin ; self-association rates ; equilibrium dissociation constant ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2022-06-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Crk proteins activate the Rap1 guanine nucleotide exchange factor C3G by segregated adaptor-dependent and -independent mechanisms

Antonio Rodríguez-Blázquez / Arturo Carabias / Alba Morán-Vaquero / Sergio de Cima / Juan R. Luque-Ortega / Carlos Alfonso / Peter Schuck / José Antonio Manso / Sandra Macedo-Ribeiro / Carmen Guerrero / José M. de Pereda

Cell Communication and Signaling, Vol 21, Iss 1, Pp 1-

2023 Volume 22

Abstract: Abstract Background C3G is a guanine nucleotide exchange factor (GEF) that activates Rap1 to promote cell adhesion. Resting C3G is autoinhibited and the GEF activity is released by stimuli that signal through tyrosine kinases. C3G is activated by ... ...

Abstract	Abstract Background C3G is a guanine nucleotide exchange factor (GEF) that activates Rap1 to promote cell adhesion. Resting C3G is autoinhibited and the GEF activity is released by stimuli that signal through tyrosine kinases. C3G is activated by tyrosine phosphorylation and interaction with Crk adaptor proteins, whose expression is elevated in multiple human cancers. However, the molecular details of C3G activation and the interplay between phosphorylation and Crk interaction are poorly understood. Methods We combined biochemical, biophysical, and cell biology approaches to elucidate the mechanisms of C3G activation. Binding of Crk adaptor proteins to four proline-rich motifs (P1 to P4) in C3G was characterized in vitro using isothermal titration calorimetry and sedimentation velocity, and in Jurkat and HEK293T cells by affinity pull-down assays. The nucleotide exchange activity of C3G over Rap1 was measured using nucleotide-dissociation kinetic assays. Jurkat cells were also used to analyze C3G translocation to the plasma membrane and the C3G-dependent activation of Rap1 upon ligation of T cell receptors. Results CrkL interacts through its SH3N domain with sites P1 and P2 of inactive C3G in vitro and in Jurkat and HEK293T cells, and these sites are necessary to recruit C3G to the plasma membrane. However, direct stimulation of the GEF activity requires binding of Crk proteins to the P3 and P4 sites. P3 is occluded in resting C3G and is essential for activation, while P4 contributes secondarily towards complete stimulation. Tyrosine phosphorylation of C3G alone causes marginal activation. Instead, phosphorylation primes C3G lowering the concentration of Crk proteins required for activation and increasing the maximum activity. Unexpectedly, optimal activation also requires the interaction of CrkL-SH2 domain with phosphorylated C3G. Conclusion Our study revealed that phosphorylation of C3G by Src and Crk-binding form a two-factor mechanism that ensures tight control of C3G activation. Additionally, the ...
Keywords	Ras-associated protein 1 ; RapGEF1 ; Signal transduction ; Tyrosine phosphorylation ; Src-homology 2 domain ; Src-homology 3 domain ; Medicine ; R ; Cytology ; QH573-671
Subject code	570
Language	English
Publishing date	2023-02-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Self-recycling and partially conservative replication of mycobacterial methylmannose polysaccharides

Ana Maranha / Mafalda Costa / Jorge Ripoll-Rozada / José A. Manso / Vanessa Miranda / Vera M. Mendes / Bruno Manadas / Sandra Macedo-Ribeiro / M. Rita Ventura / Pedro José Barbosa Pereira / Nuno Empadinhas

Communications Biology, Vol 6, Iss 1, Pp 1-

2023 Volume 17

Abstract: The mechanism of methylmannose polysaccharide (MMP) biogenesis in nontuberculous mycobacteria (NTM) is characterized, which involves an MMP-specific hydrolase (MmpH) and a rare mannosyltransferase (ManT). MmpH and ManT structures are presented. ...

Abstract	The mechanism of methylmannose polysaccharide (MMP) biogenesis in nontuberculous mycobacteria (NTM) is characterized, which involves an MMP-specific hydrolase (MmpH) and a rare mannosyltransferase (ManT). MmpH and ManT structures are presented.
Keywords	Biology (General) ; QH301-705.5
Language	English
Publishing date	2023-01-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Genetic code ambiguity modulates the activity of a C. albicans MAP kinase linked to cell wall remodeling

Fraga, Joana S / Zsuzsa Sárkány / Alexandra Silva / Inês Correia / Pedro José Barbosa Pereira / Sandra Macedo-Ribeiro

Biochimica et biophysica acta. 2019 June, v. 1867, no. 6

2019

Abstract: The human fungal pathogen Candida albicans ambiguously decodes the universal leucine CUG codon predominantly as serine but also as leucine. C. albicans has a high capacity to survive and proliferate in adverse environments but the rate of leucine ... ...

Abstract	The human fungal pathogen Candida albicans ambiguously decodes the universal leucine CUG codon predominantly as serine but also as leucine. C. albicans has a high capacity to survive and proliferate in adverse environments but the rate of leucine incorporation fluctuates in response to different stress conditions. C. albicans is adapted to tolerate this ambiguous translation through a mechanism that combines drastic decrease in CUG usage and reduction of CUG-encoded residues in conserved positions in the protein sequences. However, in a few proteins, the residues encoded by CUG codons are found in strictly conserved positions, suggesting that this genetic code alteration might have a functional impact. One such example is Cek1, a central signaling protein kinase that contains a single CUG-encoded residue at a conserved position, whose identity might regulate the correct flow of information across the MAPK cascade. Here we show that insertion of a leucine at the CUG-encoded position decreases the stability of Cek1, apparently without major structural alterations. In contrast, incorporation of a serine residue at the CUG position induces the autophosphorylation of the conserved tyrosine residue of the Cek1 231TEY233 motif, and increases its intrinsic kinase activity in vitro. These findings show that CUG ambiguity modulates the activity of Cek1, a key kinase directly linked to morphogenesis and virulence in C. albicans.
Keywords	Candida albicans ; amino acid sequences ; animal pathogenic fungi ; cell walls ; codons ; enzyme activity ; genetic code ; leucine ; mitogen-activated protein kinase ; morphogenesis ; protein phosphorylation ; proteins ; serine ; tyrosine ; virulence
Language	English
Dates of publication	2019-06
Size	p. 654-661.
Publishing place	Elsevier B.V.
Document type	Article
ZDB-ID	2918798-9
ISSN	1878-1454 ; 1570-9639
ISSN (online)	1878-1454
ISSN	1570-9639
DOI	10.1016/j.bbapap.2019.02.004
Database	NAL-Catalogue (AGRICOLA)

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Article: What a difference a cluster makes: The multifaceted roles of IscR in gene regulation and DNA recognition

Santos, Joana A / Pedro José Barbosa Pereira / Sandra Macedo-Ribeiro

Biochimica et biophysica acta. 2015 Sept., v. 1854, no. 9

2015

Abstract: Iron–sulfur clusters are essential cofactors in a myriad of metabolic pathways. Therefore, their biogenesis is tightly regulated across a variety of organisms and environmental conditions. In Gram-negative bacteria, two pathways – ISC and SUF – concur ... ...

Abstract	Iron–sulfur clusters are essential cofactors in a myriad of metabolic pathways. Therefore, their biogenesis is tightly regulated across a variety of organisms and environmental conditions. In Gram-negative bacteria, two pathways – ISC and SUF – concur for maintaining intracellular iron–sulfur cluster balance. Recently, the mechanism of iron–sulfur cluster biosynthesis regulation by IscR, an iron–sulfur cluster-containing regulator encoded by the isc operon, was found to be conserved in some Gram-positive bacteria. Belonging to the Rrf2 family of transcriptional regulators, IscR displays a single helix-turn-helix DNA-binding domain but is able to recognize two distinct DNA sequence motifs, switching its specificity upon cluster ligation. This review provides an overview of gene regulation by iron–sulfur cluster-containing sensors, in the light of the recent structural characterization of cluster-less free and DNA-bound IscR, which provided insights into the molecular mechanism of nucleotide sequence recognition and discrimination of this unique transcription factor. This article is part of a Special Issue entitled: Cofactor-dependent proteins: evolution, chemical diversity and bio-applications.
Keywords	biochemical pathways ; biogenesis ; biosynthesis ; DNA ; DNA-binding domains ; environmental factors ; Gram-negative bacteria ; Gram-positive bacteria ; nucleotide sequences ; operon ; transcription (genetics) ; transcription factors
Language	English
Dates of publication	2015-09
Size	p. 1101-1112.
Publishing place	Elsevier B.V.
Document type	Article
ZDB-ID	2918798-9
ISSN	1878-1454 ; 1570-9639
ISSN (online)	1878-1454
ISSN	1570-9639
DOI	10.1016/j.bbapap.2015.01.010
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: The structural characterization of a glucosylglycerate hydrolase provides insights into the molecular mechanism of mycobacterial recovery from nitrogen starvation

Tatiana Barros Cereija / Susana Alarico / Eva C. Lourenço / José António Manso / M. Rita Ventura / Nuno Empadinhas / Sandra Macedo-Ribeiro / Pedro José Barbosa Pereira

IUCrJ, Vol 6, Iss 4, Pp 572-

2019 Volume 585

Abstract: Bacteria are challenged to adapt to environmental variations in order to survive. Under nutritional stress, several bacteria are able to slow down their metabolism into a nonreplicating state and wait for favourable conditions. It is almost universal ... ...

Abstract	Bacteria are challenged to adapt to environmental variations in order to survive. Under nutritional stress, several bacteria are able to slow down their metabolism into a nonreplicating state and wait for favourable conditions. It is almost universal that bacteria accumulate carbon stores to survive during this nonreplicating state and to fuel rapid proliferation when the growth-limiting stress disappears. Mycobacteria are exceedingly successful in their ability to become dormant under harsh circumstances and to be able to resume growth when conditions are favourable. Rapidly growing mycobacteria accumulate glucosylglycerate under nitrogen-limiting conditions and quickly mobilize it when nitrogen availability is restored. The depletion of intracellular glucosylglycerate levels in Mycolicibacterium hassiacum (basonym Mycobacterium hassiacum) was associated with the up-regulation of the gene coding for glucosylglycerate hydrolase (GgH), an enzyme that is able to hydrolyse glucosylglycerate to glycerate and glucose, a source of readily available energy. Highly conserved among unrelated phyla, GgH is likely to be involved in bacterial reactivation following nitrogen starvation, which in addition to other factors driving mycobacterial recovery may also provide an opportunity for therapeutic intervention, especially in the serious infections caused by some emerging opportunistic pathogens of this group, such as Mycobacteroides abscessus (basonym Mycobacterium abscessus). Using a combination of biochemical methods and hybrid structural approaches, the oligomeric organization of M. hassiacum GgH was determined and molecular determinants of its substrate binding and specificity were unveiled.
Keywords	MhGgH ; GH63 ; glycoside hydrolase ; Mycolicibacterium hassiacum ; protein structure ; molecular recognition ; X-ray crystallography ; enzyme mechanism ; solution scattering ; Science ; Q
Language	English
Publishing date	2019-07-01T00:00:00Z
Publisher	International Union of Crystallography
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Leishmania infantum Asparagine Synthetase A Is Dispensable for Parasites Survival and Infectivity.

Joana Faria / Inês Loureiro / Nuno Santarém / Sandra Macedo-Ribeiro / Joana Tavares / Anabela Cordeiro-da-Silva

PLoS Neglected Tropical Diseases, Vol 10, Iss 1, p e

2016 Volume 0004365

Abstract: A growing interest in asparagine (Asn) metabolism has currently been observed in cancer and infection fields. Asparagine synthetase (AS) is responsible for the conversion of aspartate into Asn in an ATP-dependent manner, using ammonia or glutamine as a ... ...

Abstract	A growing interest in asparagine (Asn) metabolism has currently been observed in cancer and infection fields. Asparagine synthetase (AS) is responsible for the conversion of aspartate into Asn in an ATP-dependent manner, using ammonia or glutamine as a nitrogen source. There are two structurally distinct AS: the strictly ammonia dependent, type A, and the type B, which preferably uses glutamine. Absent in humans and present in trypanosomatids, AS-A was worthy of exploring as a potential drug target candidate. Appealingly, it was reported that AS-A was essential in Leishmania donovani, making it a promising drug target. In the work herein we demonstrate that Leishmania infantum AS-A, similarly to Trypanosoma spp. and L. donovani, is able to use both ammonia and glutamine as nitrogen donors. Moreover, we have successfully generated LiASA null mutants by targeted gene replacement in L. infantum, and these parasites do not display any significant growth or infectivity defect. Indeed, a severe impairment of in vitro growth was only observed when null mutants were cultured in asparagine limiting conditions. Altogether our results demonstrate that despite being important under asparagine limitation, LiAS-A is not essential for parasite survival, growth or infectivity in normal in vitro and in vivo conditions. Therefore we exclude AS-A as a suitable drug target against L. infantum parasites.
Keywords	Arctic medicine. Tropical medicine ; RC955-962 ; Public aspects of medicine ; RA1-1270
Subject code	572
Language	English
Publishing date	2016-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
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