Side chain to main chain hydrogen bonds stabilize a polyglutamine helix in a transcription factor

Escobedo, Albert; Topal, Busra; Kunze, Micha B. A.; Aranda, Juan; Chiesa, Giulio; Mungianu, Daniele; Bernardo‐Seisdedos, Ganeko; Eftekharzadeh, Bahareh; Gairì, Margarida; Pierattelli, Roberta; Felli, Isabella C.; Diercks, Tammo; Millet, Óscar; García, Jesús; Orozco, Modesto; Crehuet, Ramón; Lindorff‐Larsen, Kresten; Salvatella, Xavier

doi:10.1038/s41467-019-09923-2

Cited by 92 publications

(117 citation statements)

References 70 publications

(99 reference statements)

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“…Xavier Salvatella described the structural properties of the polyQ-AR associated with SBMA. Contrary to expectations the tract is not disordered but instead forms quite stable helices stabilized by an unusual type of hydrogen bond involving the glutamine side chain [11] . The size and the stability of these helices directly correlates with tract length, suggesting that changes in secondary structure upon polyQ tract elongation may contribute to onset of SBMA, possibly by altering that affinity that AR has for its binding partners [12] .…”

Section: Disease Mechanisms: From Ar Structure To Function In Sbmacontrasting

confidence: 83%

241st ENMC international workshop: Towards a European unifying lab for Kennedy's disease. 15–17th February, 2019 Hoofddorp, The Netherlands

Greensmith¹,

Sorarù

Pennuto

2019

Neuromuscular Disorders

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(M. Pennuto). 1 Members of the KD Consortium are listed under Participants at the end of this report. the presentations and discussions that took place during the workshop, which range from disease mechanisms, biomarker discovery, plans for an EU Registry for KD as well as an update on ongoing clinical trials. In addition, a dedicated session on the patient's perspective was presented. Kenneth Fischbeck opened the meeting with an overview of the disease. Kennedy's Disease (KD) also referred to as SBMA is a progressive X-linked neuromuscular disease characterized by bulbar and extremity muscle weakness, atrophy, and fasciculations. Affected males may show signs of androgen insensitivity, such as breast enlargement and reduced fertility. SBMA is caused by expansions of a CAG repeat in the androgen receptor (AR) gene. The disease typically presents in adult males with slowly progressive, relatively symmetrical, lower motor neuron weakness, perioral fasciculations, elevated creatine kinase, and decreased sensory potential amplitudes [1]. Common, but not invariable, manifestations are gynecomastia and a family history consistent with X-linked inheritance. Other non-neuromuscular features include Brugada syndrome [2] , urinary retention [3] , non-alcoholic fatty liver [4] , and fatigue. Primary degeneration of both motor neurons and muscle occurs in SBMA; there are clinical features of denervation and loss of motor neurons in the spinal cord and brainstem, and also increased creatine kinase and histological evidence of muscle fiber degeneration. The disease phenotype can be partially rescued in mouse models with molecular correction in either muscle or the central nervous system [5-7] .

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Section: Disease Mechanisms: From Ar Structure To Function In Sbmacontrasting

confidence: 83%

241st ENMC international workshop: Towards a European unifying lab for Kennedy's disease. 15–17th February, 2019 Hoofddorp, The Netherlands

Greensmith¹,

Sorarù

Pennuto

2019

Neuromuscular Disorders

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“…Both these residues also play a role in the amino acid context of some polyQ regions. The former is enriched in position − 1 of polyQ in vertebrates (Mier et al, 2020); it has been proposed that it promotes an alpha-helical structure towards the polyQ, making it less aggregation prone (Eftekharzadeh et al, 2016;Escobedo et al, 2019). The latter follows long human polyQ in the form of a proline-rich or polyP region (Schaefer et al, 2012), also to limit the aggregation propensity of the long polyQ (Bhattacharyya et al, 2006;Darnell et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

The features of polyglutamine regions depend on their evolutionary stability

Mier

Andrade‐Navarro

2020

Preprint

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Background Polyglutamine regions (polyQ) are one of the most studied and prevalent homorepeats in eukaryotes. They have a particular length-dependent codon usage, which relates to a characteristic CAG-slippage mechanism. Pathologically expanded tracts of polyQ are known to form aggregates and are involved in the development of several human neurodegenerative diseases. The non-pathogenic function of polyQ is to mediate protein-protein interactions via a coiled-coil pairing with an interactor. They are usually located in a helical context.Results Here we show how these known features related to polyQ depend on their stability in evolution. We have classified the polyQ regions of 60 proteomes from four distinct taxonomic groups (Insecta, Teleostei, Sauria and Mammalia) in three main categories based on their evolutionary stability. Codon usage, amino acid context, structural conformation and the protein-protein interaction capacity of polyQ from all studied taxa critically depend on the region stability.Conclusions Our results show that apart from the sequence of a polyQ, information about its orthologous sequences is needed to assess its function.

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“…Similarly, the 13 C-HSQC spectrum in panel b shows peaks corresponding to C α -H α , C β -H β and C γ -H γ . As expected for a partially disordered homorepeat, the two H β chemical shifts of the Gln are distinct, while the two H γ ones are not [ 20 , 81 ].…”

Section: Resultsmentioning

confidence: 62%

Robust Cell-Free Expression of Sub-Pathological and Pathological Huntingtin Exon-1 for NMR Studies. General Approaches for the Isotopic Labeling of Low-Complexity Proteins

et al. 2020

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The high-resolution structural study of huntingtin exon-1 (HttEx1) has long been hampered by its intrinsic properties. In addition to being prone to aggregate, HttEx1 contains low-complexity regions (LCRs) and is intrinsically disordered, ruling out several standard structural biology approaches. Here, we use a cell-free (CF) protein expression system to robustly and rapidly synthesize (sub-) pathological HttEx1. The open nature of the CF reaction allows the application of different isotopic labeling schemes, making HttEx1 amenable for nuclear magnetic resonance studies. While uniform and selective labeling facilitate the sequential assignment of HttEx1, combining CF expression with nonsense suppression allows the site-specific incorporation of a single labeled residue, making possible the detailed investigation of the LCRs. To optimize CF suppression yields, we analyze the expression and suppression kinetics, revealing that high concentrations of loaded suppressor tRNA have a negative impact on the final reaction yield. The optimized CF protein expression and suppression system is very versatile and well suited to produce challenging proteins with LCRs in order to enable the characterization of their structure and dynamics.

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Side chain to main chain hydrogen bonds stabilize a polyglutamine helix in a transcription factor

Cited by 92 publications

References 70 publications

241st ENMC international workshop: Towards a European unifying lab for Kennedy's disease. 15–17th February, 2019 Hoofddorp, The Netherlands

241st ENMC international workshop: Towards a European unifying lab for Kennedy's disease. 15–17th February, 2019 Hoofddorp, The Netherlands

The features of polyglutamine regions depend on their evolutionary stability

Robust Cell-Free Expression of Sub-Pathological and Pathological Huntingtin Exon-1 for NMR Studies. General Approaches for the Isotopic Labeling of Low-Complexity Proteins

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