The first 17 amino acids of Huntingtin modulate its sub-cellular localization, aggregation and effects on calcium homeostasis

Rockabrand, Erica; Slepko, Natalia; Pantalone, A.; Nukala, Vidya N.; Kazantsev, Aleksey G.; Marsh, J. Lawrence; Sullivan, Patrick G.; Steffan, Joan S.; Sensi, Stefano L.; Thompson, Leslie M.

doi:10.1093/hmg/ddl440

Cited by 253 publications

(316 citation statements)

References 95 publications

Supporting

Mentioning

295

Contrasting

Unclassified

Order By: Relevance

“…It has been demonstrated that the addition of a poly(P) sequence to the C terminus of a poly(Q) peptide influences the conformation of the poly(Q) domain and alters the rate of aggregation (13). The poly(P) domain has also been shown to facilitate the ability of Nt17 to associate specifically with the ER and Golgi (22). Flanking poly(P) sequences induce a PPII-like helical structure on the adjacent poly(Q) domain, which can increase the length of the poly(Q) domain that is needed to induce fibril formation (14,48).…”

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

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

“…Additionally, deletion of N17 results in nuclear accumulation of Htt fragments, showing the importance of N17 in cytoplasmic localization (20). Work by others has suggested that N17 contains a temperature-sensitive cytoplasm retention signal that mediates association with the endoplasmic reticulum and mitochondria (13,18,19). Given the critical role of nuclear localization in Htt toxicity (20,21), we sought to define the mechanism for the effects of N17 on the trafficking of N-terminal Htt fragments.…”

Section: Huntington Disease (Hd)mentioning

confidence: 99%

An N-terminal Nuclear Export Signal Regulates Trafficking and Aggregation of Huntingtin (Htt) Protein Exon 1*

Zheng¹,

Li²,

Holmes³

et al. 2013

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background: Trafficking of huntingtin (Htt) fragments influences its toxicity. Results: A leucine-rich NES lies within the first 17 amino acids (N17) of Htt that controls subcellular localization and aggregation. Conclusion: The NES functions in cis and regulates the aggregation of Htt. Significance: This helps explain the mechanism of subcellular trafficking and aggregation of Htt fragments and may help elucidate molecular mechanisms of Htt toxicity.

show abstract

“…The polyglutamine tract of huntingtin is flanked on the aminoterminal side by the first 17 amino acids, termed N17, an amphipathic alpha-helical targeting domain that can mediate huntingtin localization to membranes (9,10). The N17 domain can be modified posttranslationally at multiple residues (11)(12)(13)(14).…”

mentioning

confidence: 99%

Polyglutamine domain flexibility mediates the proximity between flanking sequences in huntingtin

Caron

Desmond

Xia

et al. 2013

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

131

151

View full text Add to dashboard Cite

Huntington disease (HD) is a neurodegenerative disorder caused by a CAG expansion within the huntingtin gene that encodes a polymorphic glutamine tract at the amino terminus of the huntingtin protein. HD is one of nine polyglutamine expansion diseases. The clinical threshold of polyglutamine expansion for HD is near 37 repeats, but the mechanism of this pathogenic length is poorly understood. Using Förster resonance energy transfer, we describe an intramolecular proximity between the N17 domain and the downstream polyproline region that flanks the polyglutamine tract of huntingtin. Our data support the hypothesis that the polyglutamine tract can act as a flexible domain, allowing the flanking domains to come into close spatial proximity. This flexibility is impaired with expanded polyglutamine tracts, and we can detect changes in huntingtin conformation at the pathogenic threshold for HD. Altering the structure of N17, either via phosphomimicry or with small molecules, also affects the proximity between the flanking domains. The structural capacity of N17 to fold back toward distal regions within huntingtin requires an interacting protein, protein kinase C and casein kinase 2 substrate in neurons 1 (PACSIN1). This protein has the ability to bind both N17 and the polyproline region, stabilizing the interaction between these two domains. We also developed an antibody-based FRET assay that can detect conformational changes within endogenous huntingtin in wild-type versus HD fibroblasts. Therefore, we hypothesize that wild-type length polyglutamine tracts within huntingtin can form a flexible domain that is essential for proper functional intramolecular proximity, conformations, and dynamics.polyglutamine diseases | conformational switching | FLIM-FRET | neurodegeneration | fluorescence lifetime imaging microscopy H untington disease (HD) is an autosomal dominant, progressive neurodegenerative disorder caused by the expansion of a CAG trinucleotide repeat within the huntingtin (HTT) gene (1). The pathogenic threshold of CAG expansion is ∼37 repeats, with increased repeats leading to an earlier age-onset of HD (2-4). This CAG mutation results in an expanded polyglutamine tract in the amino terminus of the gene's protein product, huntingtin (1). To date, no phenotypes at the level of huntingtin molecular biology or animal models can be attributed to polyglutamine lengths near the human pathogenic disease threshold (5).Polyglutamine or glutamine-rich domains are also found in transcription factors such as the Sp-family and cAMP response element-binding protein (CREB) and are defined as proteinprotein interaction motifs used to scaffold and regulate transcription by RNA polymerase II (6, 7). In the transducin-like enhancer of split (TLE) corepressor proteins, the glutamine-rich domains are thought to allow dimerization (8). However, the role of polyglutamine in proteins such as huntingtin may be distinct from that of a protein-protein interaction or dimerization domain.The polyglutamine tract of huntingtin is flanked on...

show abstract

The first 17 amino acids of Huntingtin modulate its sub-cellular localization, aggregation and effects on calcium homeostasis

Cited by 253 publications

References 95 publications

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

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

An N-terminal Nuclear Export Signal Regulates Trafficking and Aggregation of Huntingtin (Htt) Protein Exon 1*

Polyglutamine domain flexibility mediates the proximity between flanking sequences in huntingtin

Contact Info

Product

Resources

About