Flanking Polyproline Sequences Inhibit β-Sheet Structure in Polyglutamine Segments by Inducing PPII-like Helix Structure

Darnell, Gregory D.; Orgel, Joseph P. R. O.; Pahl, R.; Meredith, Stephen C.

doi:10.1016/j.jmb.2007.09.023

Cited by 151 publications

(217 citation statements)

References 109 publications

(123 reference statements)

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“…This may indicate that such a branched structure may function by serving as a steric impediment to the formation of higher order polyglutamine ␤-sheet structures. An analogous effect has been observed for flanking polyproline tracts, which can inhibit ␤-sheet structure in polyglutamine segments (76). Alternatively, SUMO modification of the SC motifs in AR may prevent proteolytic steps that are thought to be involved in the generation of toxic polyglutamine-containing fragments (77,78).…”

Section: Discussionmentioning

confidence: 74%

Small Ubiquitin-like Modifier (SUMO) Modification of the Androgen Receptor Attenuates Polyglutamine-mediated Aggregation

Mukherjee¹,

Thomas

Dadgar

et al. 2009

Journal of Biological Chemistry

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The neurodegenerative disorder spinal and bulbar muscular atrophy or Kennedy disease is caused by a CAG trinucleotide repeat expansion within the androgen receptor (AR) gene. The resulting expanded polyglutamine tract in the N-terminal region of the receptor renders AR prone to ligand-dependent misfolding and formation of oligomers and aggregates that are linked to neuronal toxicity. How AR misfolding is influenced by post-translational modifications, however, is poorly understood. AR is a target of SUMOylation, and this modification inhibits AR activity in a promoter context-dependent manner. SUMOylation is up-regulated in response to multiple forms of cellular stress and may therefore play an important cytoprotective role. Consistent with this view, we find that gratuitous enhancement of overall SUMOylation significantly reduced the formation of polyglutamine-expanded AR aggregates without affecting the levels of the receptor. Remarkably, this effect requires SUMOylation of AR itself because it depends on intact AR SUMOylation sites. Functional analyses, however, indicate that the protective effects of enhanced AR SUMOylation are not due to alterations in AR transcriptional activity because a branched protein structure in the appropriate context of the N-terminal region of AR is necessary to antagonize aggregation but not for inhibiting AR transactivation. Remarkably, small ubiquitin-like modifier (SUMO) attenuates AR aggregation through a unique mechanism that does not depend on critical features essential for its interaction with canonical SUMO binding motifs. Our findings therefore reveal a novel function of SUMOylation and suggest that approaches that enhance AR SUMOylation may be of clinical use in polyglutamine expansion diseases.Spinal and bulbar muscular atrophy (SBMA), 2 or Kennedy disease, is an inherited degenerative disorder of lower motor neurons (1, 2). SBMA is characterized by muscle cramps and fasciculations followed by progressive weakness and atrophy of the proximal limb and bulbar muscles (3-5). The causative genetic alteration is an expansion in the length of a CAG trinucleotide repeat within the coding sequence of the androgen receptor (AR) gene, leading to an expanded polyglutamine tract in the N-terminal transcriptional regulatory domain of the receptor. A similar expansion within the coding sequence of a set of additional genes is responsible for other members of the polyglutamine class of protein folding diseases (6, 7), which include Huntington disease, several autosomal dominant spinocerebellar ataxias (SCAs) (8), and dentatorubral-pallidoluysian atrophy (9, 10).The length of the CAG repeat within AR is correlated to the severity of SBMA. Although the normal repeat length is highly polymorphic and ranges between 9 and 36 copies, overt disease is associated with lengths in the range of 38 -62 repeats. The presence of an expanded polyglutamine tract within AR renders the protein prone to hormone-dependent misfolding, oligomerization, and aggregation and to the formation of microscopica...

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Section: Discussionmentioning

confidence: 74%

Small Ubiquitin-like Modifier (SUMO) Modification of the Androgen Receptor Attenuates Polyglutamine-mediated Aggregation

Mukherjee¹,

Thomas

Dadgar

et al. 2009

Journal of Biological Chemistry

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“…This behavior could be due to residual polyproline II structure. The highly proline-rich C terminus has been predicted (21,43,44), but not shown directly, to take up such a structure in HDx1 fibrils.…”

Section: Resultsmentioning

confidence: 99%

Structural Features and Domain Organization of Huntingtin Fibrils

Bugg

Isas

Fischer

et al. 2012

Journal of Biological Chemistry

150

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Background:The structure of fibrils formed in Huntington disease remains unknown. Results: Local structure and domain organization of huntingtin exon 1 fibrils were determined by EPR spectroscopy. Conclusion: In contrast to the C terminus, the N terminus, and polyglutamine core regions become closely packed, without forming a parallel, in-register structure. Significance:The results provide structural constraints and insight into how adjacent domains affect polyglutamine structure.

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“…We believe that these Pro residues act as conformational stabilizers and offer improved resistance to TFE-induced folding. 39,40 This resistance to folding may play a role in the function of the PPII containing central domain within rP172, such as the participation in intermolecular contacts that lead to self-assembly at appropriate protein concentrations, or, facilitate the folding and/or stabilization of the adjacent N-and Ctermini. 9,39,40,45 The second group of Pro residues are a limited subset (P2, P127, P130, P139, P154, P157, P162), which exhibit significant conformational sensitivity to TFE (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…38 However, given that only limited regions within these two PPII domains experience TFE-induced folding transitions, it is clear that the majority of these Pro, Gln rich regions within the central domain are resistant to TFE ''solvent engineering,'' most likely as a result of the strong stabilization features of these sequences. 39,40 Conformational response of Pro residues It is known from earlier studies that TFE affects Pro imido ring dynamics, conformation, and cis trans interconversion. 28,29,33,38 Since amelogenins contain a significant number of Pro residues (e.g., rP172 ¼ 40 Pro, or 23% of the total sequence, Fig.…”

Section: Localization Of Folding Within Rp172mentioning

confidence: 99%

Probing the self‐association, intermolecular contacts, and folding propensity of amelogenin

et al. 2011

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Amelogenins are an intrinsically disordered protein family that plays a major role in the development of tooth enamel, one of the most highly mineralized materials in nature. Monomeric porcine amelogenin possesses random coil and residual secondary structures, but it is not known which sequence regions would be conformationally attractive to potential enamel matrix targets such as other amelogenins (self-assembly), other matrix proteins, cell surfaces, or biominerals. To address this further, we investigated recombinant porcine amelogenin (rP172) using ''solvent engineering'' techniques to simultaneously promote native-like structure and induce amelogenin oligomerization in a manner that allows identification of intermolecular contacts between amelogenin molecules. We discovered that in the presence of 2,2,2-trifluoroethanol (TFE) significant folding transitions and stabilization occurred primarily within the N-and C-termini, while the polyproline Type II central domain was largely resistant to conformational transitions. Seven Pro residues (P2, P127, P130, P139, P154, P157, P162) exhibited conformational response to TFE, and this indicates these Pro residues act as folding enhancers in rP172. The remaining Pro residues resisted TFE perturbations and thus act as conformational stabilizers. We also noted that TFE induced rP172 self-association via the formation of intermolecular contacts involving P4-H6, V19-P33, and E40-T58 regions of the N-terminus. Collectively, these results confirm that the Nand C-termini of amelogenin are conformationally responsive and represent potential interactive sites for amelogenin-target interactions during enamel matrix mineralization. Conversely, the Pro, Gln central domain is resistant to folding and this may have important functional significance for amelogenin.Abbreviations: AQ-rP172, uniformly labeled 13 C, 15 N rP172 in 90% v/v UDDW, 10% v/v D 2 O, pH 3.8; CD, circular dichroism; DLS, dynamic light scattering; HSQC, heteronuclear single quantum coherence; IDP, intrinsically disordered protein; rP172, recombinant porcine amelogenin; 70-rP172, uniformly labeled 13 C, 15 N rP172 in 30% v/v UDDW, 70% v/v 2,2,2-trifluoroethanol, pH 3.8; RC, random coil; SSP, secondary structure propensity score; TFE, 2,2,2-trifluoroethanol; UDDW, Milli-Q pure unbuffered deionized distilled water.

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Flanking Polyproline Sequences Inhibit β-Sheet Structure in Polyglutamine Segments by Inducing PPII-like Helix Structure

Cited by 151 publications

References 109 publications

Small Ubiquitin-like Modifier (SUMO) Modification of the Androgen Receptor Attenuates Polyglutamine-mediated Aggregation

Small Ubiquitin-like Modifier (SUMO) Modification of the Androgen Receptor Attenuates Polyglutamine-mediated Aggregation

Structural Features and Domain Organization of Huntingtin Fibrils

Probing the self‐association, intermolecular contacts, and folding propensity of amelogenin

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