scholarly journals Huntingtin fibrils with different toxicity, structure, and seeding potential can be interconverted

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
J. Mario Isas ◽  
Nitin K. Pandey ◽  
Hui Xu ◽  
Kazuki Teranishi ◽  
Alan K. Okada ◽  
...  
Keyword(s):  
Neurodegenerative Disease ◽  
Huntington's Disease ◽  
Protein Interactions ◽  
Film Formation ◽  
Protein Protein Interactions ◽  
Huntingtin Protein ◽  
Rich Domain ◽  
The Difference ◽  
Degree Of Entanglement ◽  
In Cells

AbstractThe first exon of the huntingtin protein (HTTex1) important in Huntington’s disease (HD) can form cross-β fibrils of varying toxicity. We find that the difference between these fibrils is the degree of entanglement and dynamics of the C-terminal proline-rich domain (PRD) in a mechanism analogous to polyproline film formation. In contrast to fibril strains found for other cross-β fibrils, these HTTex1 fibril types can be interconverted. This is because the structure of their polyQ fibril core remains unchanged. Further, we find that more toxic fibrils of low entanglement have higher affinities for protein interactors and are more effective seeds for recombinant HTTex1 and HTTex1 in cells. Together these data show how the structure of a framing sequence at the surface of a fibril can modulate seeding, protein-protein interactions, and thereby toxicity in neurodegenerative disease.

scholarly journals Huntingtin fibrils with different toxicity, structure, and seeding potential can be reversibly interconverted

2019 ◽  
Author(s):  
J. Mario Isas ◽  
Nitin K. Pandey ◽  
Kazuki Teranishi ◽  
Alan K. Okada ◽  
Anise Applebaum ◽  
...  
Keyword(s):  
Neurodegenerative Disease ◽  
Huntington's Disease ◽  
Protein Interactions ◽  
Film Formation ◽  
Protein Protein Interactions ◽  
Huntingtin Protein ◽  
Rich Domain ◽  
The Difference ◽  
Degree Of Entanglement ◽  
In Cells

AbstractThe first exon of the huntingtin protein (HTTex1) important in Huntington’s Disease (HD) can form cross-β fibrils of varying toxicity. We find that the difference between these fibrils is the degree of entanglement and dynamics of the C-terminal proline-rich domain (PRD) in a mechanism analogous to polyproline film formation. In contrast to fibril strains found for other cross-β fibrils, these HTTex1 fibril types can be reversibly interconverted. This is because the structure of their polyQ fibril core remains unchanged. Further, we find that more toxic fibrils of low entanglement have higher affinities for protein interactors and are more effective seeds for recombinant HTTex1 and HTTex1 in cells. Together these data show how the structure of a framing sequence at the surface of a fibril can modulate seeding, protein-protein interactions, and thereby toxicity in neurodegenerative disease.

scholarly journals The pathobiology of perturbed mutant huntingtin protein–protein interactions in Huntington's disease

2019 ◽  
Vol 151 (4) ◽  
pp. 507-519 ◽  
Author(s):  
Erich E. Wanker ◽  
Anne Ast ◽  
Franziska Schindler ◽  
Philipp Trepte ◽  
Sigrid Schnoegl
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Protein Interactions ◽  
Mutant Huntingtin ◽  
Protein Protein Interactions ◽  
Huntingtin Protein ◽  
Mutant Huntingtin Protein

scholarly journals Integrating Structural Information to Study the Dynamics of Protein-Protein Interactions in Cells

Structure ◽  
2018 ◽  
Vol 26 (10) ◽  
pp. 1414-1424.e3 ◽  
Author(s):  
Bo Wang ◽  
Zhong-Ru Xie ◽  
Jiawen Chen ◽  
Yinghao Wu
Keyword(s):  
Protein Interactions ◽  
Structural Information ◽  
Protein Protein Interactions ◽  
In Cells

Direct Monitoring of the Inhibition of Protein-Protein Interactions in Cells by Translocation of PKCδ Fusion Proteins

2011 ◽  
Vol 50 (6) ◽  
pp. 1314-1317 ◽  
Author(s):  
Kyung-Bok Lee ◽  
Jung Me Hwang ◽  
Insung S. Choi ◽  
Jaerang Rho ◽  
Jong-Soon Choi ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Fusion Proteins ◽  
Protein Protein Interactions ◽  
In Cells

Hypothesis: huntingtin may function in membrane association and vesicular traffickingThis paper is one of a selection of papers published in this Special Issue, entitled CSBMCB — Membrane Proteins in Health and Disease.

2006 ◽  
Vol 84 (6) ◽  
pp. 912-917 ◽  
Author(s):  
Ray Truant ◽  
Randy Atwal ◽  
Anjee Burtnik
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Protein Interactions ◽  
Cell Biology ◽  
Genetic Disorder ◽  
Scaffolding Protein ◽  
Membrane Association ◽  
Protein Protein Interactions ◽  
Polyglutamine Expansion ◽  
Exact Function

Huntington’s disease is a progressive neurodegenerative genetic disorder that is caused by a CAG triplet-repeat expansion in the first exon of the IT15 gene. This CAG expansion results in polyglutamine expansion in the 350 kDa huntingtin protein. The exact function of huntingtin is unknown. Understanding the pathological triggers of mutant huntingtin, and distinguishing the cause of disease from downstream effects, is critical to designing therapeutic strategies and defining long- and short-term goals of therapy. Many studies that have sought to determine the functions of huntingtin by determining huntingtin’s protein–protein interactions have been published. Through these studies, huntingtin has been seen to interact with a large number of proteins, and is likely a scaffolding protein for protein–protein interactions. Recently, using imaging, integrative proteomics, and cell biology, huntingtin has been defined as a membrane-associated protein, with activities related to axonal trafficking of vesicles and mitochondria. These functions have also been attributed to some huntingtin-interacting proteins. Additionally, discoveries of a membrane association domain and a palmitoylation site in huntingtin reinforce the fact that huntingtin is membrane associated. In Huntington’s disease mouse and fly models, axonal vesicle trafficking is inhibited, and lack of proper uptake of neurotrophic factors may be an important pathological trigger leading to striatal cell death in Huntington’s disease. Here we discuss recent advances from many independent groups and methodologies that are starting to resolve the elusive function of huntingtin in vesicle transport, and evidence that suggests that huntingtin may be directly involved in membrane interactions.

scholarly journals Thyroid stimulating autoantibody M22 mimics TSH binding to the TSH receptor leucine rich domain: a comparative structural study of protein–protein interactions

2009 ◽  
Vol 42 (5) ◽  
pp. 381-395 ◽  
Author(s):  
R Núñez Miguel ◽  
J Sanders ◽  
D Y Chirgadze ◽  
J Furmaniak ◽  
B Rees Smith
Keyword(s):  
Crystal Structure ◽  
Protein Interactions ◽  
Hydrophobic Interactions ◽  
Human Monoclonal Antibody ◽  
Tsh Receptor ◽  
Salt Bridges ◽  
Protein Protein Interactions ◽  
Rich Domain ◽  
Candidate Target ◽  
Comparative Model

The TSH receptor (TSHR) ligands M22 (a thyroid stimulating human monoclonal antibody) and TSH, bind to the concave surface of the leucine rich repeats domain (LRD) of the TSHR and here, we show that M22 mimics closely the binding of TSH. We compared interactions produced by M22 with the TSHR in the M22–TSHR crystal structure (2.55 Å resolution) and produced by TSH with the TSHR in a TSH–TSHR comparative model. The crystal structure of the TSHR and a comparative model of TSH based on the crystal structure of FSH were used as components to build the TSH–TSHR model. This model was built based on the FSH–FSH receptor structure (2.9 Å) and then the structure of the TSHR in the model was replaced by the TSHR crystal structure. The analysis shows that M22 light chain mimics the TSHβ chain in its interaction with TSHR LRD, while M22 heavy chain mimics the interactions of the TSHα chain. The M22–TSHR complex contains a greater number of hydrogen bonds and salt bridges and fewer hydrophobic interactions than the TSH–TSHR complex, consistent with a higher M22 binding affinity. Furthermore, the surface area formed by TSHR residues N208, Q235, R255, and N256 has been identified as a candidate target region for small molecules which might selectively block binding of autoantibodies to the TSHR.

scholarly journals Genetic code expansion and photocross-linking identify different β-arrestin binding modes to the angiotensin II type 1 receptor

2019 ◽  
Vol 294 (46) ◽  
pp. 17409-17420 ◽  
Author(s):  
Laurence Gagnon ◽  
Yubo Cao ◽  
Aaron Cho ◽  
Dana Sedki ◽  
Thomas Huber ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Protein Interactions ◽  
Unnatural Amino Acid ◽  
Binding Modes ◽  
Protein Protein Interactions ◽  
Contact Mode ◽  
Biased Signaling ◽  
Genetic Code Expansion ◽  
In Cells

The angiotensin II (AngII) type 1 receptor (AT1R) is a member of the G protein–coupled receptor (GPCR) family and binds β-arrestins (β-arrs), which regulate AT1R signaling and trafficking. These processes can be biased by different ligands or mutations in the AGTR1 gene. As for many GPCRs, the exact details for AT1R–β-arr interactions driven by AngII or β-arr–biased ligands remain largely unknown. Here, we used the amber-suppression technology to site-specifically introduce the unnatural amino acid (UAA) p-azido-l-phenylalanine (azF) into the intracellular loops (ICLs) and the C-tail of AT1R. Our goal was to generate competent photoreactive receptors that can be cross-linked to β-arrs in cells. We performed UV-mediated photolysis of 25 different azF-labeled AT1Rs to cross-link β-arr1 to AngII-bound receptors, enabling us to map important contact sites in the C-tail and in the ICL2 and ICL3 of the receptor. The extent of AT1R–β-arr1 cross-linking among azF-labeled receptors differed, revealing variability in β-arr's contact mode with the different AT1R domains. Moreover, the signature of ligated AT1R–β-arr complexes from a subset of azF-labeled receptors also differed between AngII and β-arr–biased ligand stimulation of receptors and between azF-labeled AT1R bearing and that lacking a bias signaling mutation. These observations further implied distinct interaction modalities of the AT1R–β-arr1 complex in biased signaling conditions. Our findings demonstrate that this photocross-linking approach is useful for understanding GPCR–β-arr complexes in different activation states and could be extended to study other protein–protein interactions in cells.

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