Secondary Structure of Huntingtin Amino-Terminal Region

Kim, Mee Whi; Chelliah, Yogarany; Kim, Sang Woo; Otwinowski, Zbyszek; Bezprozvanny, Ilya

doi:10.1016/j.str.2009.08.002

Cited by 227 publications

(337 citation statements)

References 48 publications

Supporting

Mentioning

294

Contrasting

Unclassified

Order By: Relevance

“…Unfortunately, these studies have reported contradictory observations regarding the conformational preferences of the HR. Similar observations have been obtained from crystallographic studies of non‐aggregated poly‐Q constructs: while a peptide of 10 consecutive glutamines in complex with an antibody showed an extended structure,14 a construct with 17 Qs in the context of htt exon1 showed multiple conformations (helix, random coil, and extended loop), and only the initial residues were visible on the map 15. More recently, Baias et al.…”

supporting

confidence: 76%

A General Strategy to Access Structural Information at Atomic Resolution in Polyglutamine Homorepeats

et al. 2018

View full text Add to dashboard Cite

Homorepeat (HR) proteins are involved in key biological processes and multiple pathologies, however their high‐resolution characterization has been impaired due to their homotypic nature. To overcome this problem, we have developed a strategy to isotopically label individual glutamines within HRs by combining nonsense suppression and cell‐free expression. Our method has enabled the NMR investigation of huntingtin exon1 with a 16‐residue polyglutamine (poly‐Q) tract, and the results indicate the presence of an N‐terminal α‐helix at near neutral pH that vanishes towards the end of the HR. The generality of the strategy was demonstrated by introducing a labeled glutamine into a pathological version of huntingtin with 46 glutamines. This methodology paves the way to decipher the structural and dynamic perturbations induced by HR extensions in poly‐Q‐related diseases. Our approach can be extended to other amino acids to investigate biological processes involving proteins containing low‐complexity regions (LCRs).

show abstract

supporting

confidence: 76%

A General Strategy to Access Structural Information at Atomic Resolution in Polyglutamine Homorepeats

et al. 2018

View full text Add to dashboard Cite

show abstract

“…Our studies indicate a role of Nt17 in the interaction between htt and lipid membranes. Nt17 forms an amphipathic ␣-helical structure (20), which can influence the first few glutamines in the poly(Q) domain to adopt an ␣-helical conformation (41). The amphipathic properties of the Nt17 ␣-helix (Fig.…”

Section: Discussionmentioning

confidence: 99%

The Interaction of Polyglutamine Peptides with Lipid Membranes Is Regulated by Flanking Sequences Associated with Huntingtin

Burke

Kauffman

Umbaugh

et al. 2013

Journal of Biological Chemistry

157

View full text Add to dashboard Cite

“…A solved crystal structure of the HTT exon 1 gene product with 17 glutamine repeats fused with maltose binding protein shows that the NT17 segment becomes α-helical (29). The NT17 tract has been shown to be critical for the formation of α-helix-rich oligomeric intermediates by Jayaraman et al (14).…”

Section: N-terminal Region Facilitates the Aggregation Of Nt 17 -Q 20mentioning

confidence: 99%

Aggregation landscapes of Huntingtin exon 1 protein fragments and the critical repeat length for the onset of Huntington’s disease

Chen

Wolynes

2017

Proc. Natl. Acad. Sci. U.S.A.

104

View full text Add to dashboard Cite

Huntington's disease (HD) is a neurodegenerative disease caused by an abnormal expansion in the polyglutamine (polyQ) track of the Huntingtin (HTT) protein. The severity of the disease depends on the polyQ repeat length, arising only in patients with proteins having 36 repeats or more. Previous studies have shown that the aggregation of N-terminal fragments (encoded by HTT exon 1) underlies the disease pathology in mouse models and that the HTT exon 1 gene product can self-assemble into amyloid structures. Here, we provide detailed structural mechanisms for aggregation of several protein fragments encoded by HTT exon 1 by using the associative memory, water-mediated, structure and energy model (AWSEM) to construct their free energy landscapes. We find that the addition of the N-terminal 17-residue sequence (NT 17 ) facilitates polyQ aggregation by encouraging the formation of prefibrillar oligomers, whereas adding the C-terminal polyproline sequence (P 10 ) inhibits aggregation. The combination of both terminal additions in HTT exon 1 fragment leads to a complex aggregation mechanism with a basic core that resembles that found for the aggregation of pure polyQ repeats using AWSEM. At the extrapolated physiological concentration, although the grand canonical free energy profiles are uphill for HTT exon 1 fragments having 20 or 30 glutamines, the aggregation landscape for fragments with 40 repeats has become downhill. This computational prediction agrees with the critical length found for the onset of HD and suggests potential therapies based on blocking early binding events involving the terminal additions to the polyQ repeats.Huntington's disease | aggregation | solubility | aggregation free energy landscape | critical length H untingtin (HTT) is a huge protein (3,100 amino acid residues) that has been implicated in a variety of physiological functions (1, 2). Having an expanded polyglutamine (polyQ) region of 36 or more glutamine residues in the N terminus of HTT leads to Huntington's disease as witnessed by the deposition of large intracellular protein aggregates or inclusion bodies, which are comprised primarily of N-terminal fragments coded by the exon 1 sequence of the mutant HTT (2-5). These N-terminal fragments, each composed of an N-terminal 17-residue sequence (NT17), a polyQ sequence that has expanded in length, and a proline-rich region afterward, originate from proteolysis of HTT (2, 3). The aggregation of the HTT exon 1 product is, therefore, believed to cause Huntington's disease. Clinical studies have shown an inverse correlation between polyQ length and age of disease onset (5). By implicating polymer physics in the disease process, this regularity has intrigued biophysicists for decades.Expanded polyQ sequences, more generally, are associated with nine known neurodegenerative diseases (4). Biophysical chemists have, therefore, focused on first understanding the aggregation of pure polyQ peptides. The rate of aggregation of polyQ peptides is length-dependent, and primary nucleation is rate-limiti...

show abstract

Secondary Structure of Huntingtin Amino-Terminal Region

Cited by 227 publications

References 48 publications

A General Strategy to Access Structural Information at Atomic Resolution in Polyglutamine Homorepeats

A General Strategy to Access Structural Information at Atomic Resolution in Polyglutamine Homorepeats

The Interaction of Polyglutamine Peptides with Lipid Membranes Is Regulated by Flanking Sequences Associated with Huntingtin

Aggregation landscapes of Huntingtin exon 1 protein fragments and the critical repeat length for the onset of Huntington’s disease

Contact Info

Product

Resources

About