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Huntingtin's spherical solenoid structure enables polyglutamine tract-dependent modulation of its structure and function.

ABSTRACT: The polyglutamine expansion in huntingtin protein causes Huntington's disease. Here, we investigated structural and biochemical properties of huntingtin and the effect of the polyglutamine expansion using various biophysical experiments including circular dichroism, single-particle electron microscopy and cross-linking mass spectrometry. Huntingtin is likely composed of five distinct domains and adopts a spherical ?-helical solenoid where the amino-terminal and carboxyl-terminal regions fold to contain a circumscribed central cavity. Interestingly, we showed that the polyglutamine expansion increases ?-helical properties of huntingtin and affects the intramolecular interactions among the domains. Our work delineates the structural characteristics of full-length huntingtin, which are affected by the polyglutamine expansion, and provides an elegant solution to the apparent conundrum of how the extreme amino-terminal polyglutamine tract confers a novel property on huntingtin, causing the disease.

SUBMITTER: Vijayvargia R

PROVIDER: S-EPMC4846397 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Huntingtin's spherical solenoid structure enables polyglutamine tract-dependent modulation of its structure and function.

Vijayvargia Ravi R Epand Raquel R Leitner Alexander A Jung Tae-Yang TY Shin Baehyun B Jung Roy R Lloret Alejandro A Singh Atwal Randy R Lee Hyeongseok H Lee Jong-Min JM Aebersold Ruedi R Hebert Hans H Song Ji-Joon JJ Seong Ihn Sik IS

eLife 20160322

The polyglutamine expansion in huntingtin protein causes Huntington's disease. Here, we investigated structural and biochemical properties of huntingtin and the effect of the polyglutamine expansion using various biophysical experiments including circular dichroism, single-particle electron microscopy and cross-linking mass spectrometry. Huntingtin is likely composed of five distinct domains and adopts a spherical α-helical solenoid where the amino-terminal and carboxyl-terminal regions fold to ...[more]

PMID: 27003594

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Project description:Liposomal spherical nucleic acids (L-SNAs) show significant promise as cancer immunotherapeutics. L-SNAs are highly modular nanoscale assemblies defined by a dense, upright radial arrangement of oligonucleotides around a liposomal core. Herein, we establish a set of L-SNA design rules by studying the biological and immunological properties of L-SNAs as a function of liposome composition. To achieve this, we synthesized liposomes where the lipid phosphatidylcholine headgroup was held constant, while the diacyl lipid tail chain length and degree of saturation were varied, using either 1,2-dioleylphosphatidylcholine (DOPC), 1,2-dimyristoyl-phosphatidylcholine (DMPC), 1,2-dipalmitoylphosphatidylcholine (DPPC), or 1,2-distearoyl-phosphatidylcholine (DSPC). These studies show that the identity of the constituent lipid dictates the DNA loading, cellular uptake, serum stability, in vitro immunostimulatory activity, and in vivo lymph node accumulation of the L-SNA. Furthermore, in the 4T1 mouse model of triple-negative breast cancer (TNBC), the subcutaneous administration of immunostimulatory L-SNAs synthesized with DPPC significantly decreases the production of lung metastases and delays tumor growth as compared to L-SNAs synthesized using DOPC, due to the enhanced stability of L-SNAs synthesized with DPPC over those synthesized with DOPC. Moreover, the inclusion of cell lysates derived from Py8119 TNBC cells as antigen sources in L-SNAs leads to a significant increase in antitumor efficacy in the Py8119 model when lysates are encapsulated in the cores of L-SNAs synthesized with DPPC rather than DOPC, presumably due to increased codelivery of adjuvant and antigen to dendritic cells in vivo. This difference is further amplified when using lysates from oxidized Py8119 cells as a more potent antigen source, revealing synergy between the lysate preparation method and liposome composition in synthesizing immunotherapeutic L-SNAs. Together, this work shows that the biological properties and immunomodulatory activity of L-SNAs can be modulated by exchanging liposome components, providing another handle for the rational design of nanoscale immunotherapeutics.

Project description:MotivationSolenoid proteins are emerging as a protein class with properties intermediate between structured and intrinsically unstructured proteins. Containing repeating structural units, solenoid proteins are expected to share sequence similarities. However, in many cases, the sequence similarities are weak and non-detectable. Moreover, solenoids can be degenerated and widely vary in the number of units. So that it is difficult to detect them. Recently, several solenoid repeats detection methods have been proposed, such as self-alignment of the sequence, spectral analysis and discrete Fourier transform of sequence. Although these methods have shown good performance on certain data sets, they often fail to detect repeats with weak similarities. In this article, we propose a new approach to recognize solenoid repeats and non-solenoid proteins using stationary wavelet packet transform (SWPT). Our method associates with three advantages: (i) naturally representing five main factors of protein structure and properties by wavelet analysis technique; (ii) extracting novel wavelet features that can capture hidden components from solenoid sequence similarities and distinguish them from global proteins; (iii) obtaining statistics features that capture repeating motifs of solenoid proteins.ResultsOur method analyzes the characteristics of amino acid sequence in both spectral and temporal domains using SWPT. Both global and local information of proteins are captured by SWPT coefficients. We obtain and integrate wavelet-based features and statistics-based features of amino acid sequence to improve the classification task. Our proposed method is evaluated by comparing to state-of-the-art methods such as HHrepID and REPETITA. The experimental results show that our algorithm consistently outperforms them in areas under ROC curve. At the same false positive rate, the sensitivity of our WAVELET method is higher than other methods.Availabilityhttp://www.naaan.org/anvo/Software/Software.htm.

Dataset Information

Huntingtin's spherical solenoid structure enables polyglutamine tract-dependent modulation of its structure and function.

Publications

Huntingtin's spherical solenoid structure enables polyglutamine tract-dependent modulation of its structure and function.

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