Journal
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Volume 142, Issue 17, Pages 7976-7986Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jacs.0c02263
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Funding
- European Research Council under the European Union's H2020 Framework Programme (2014-2020)/ERC Grant [648030]
- Labex EpiGenMed, an Investissements d'avenir program [ANR-10LABX-12-01]
- GPCteR [ANR-17CE11-0022-01]
- French National Research Agency [ANR10-INBS-04-01, ANR-10-INBS-05]
- TGIR-RMN-THC Fr3050 CNRS
- Spanish MINECO [CTQ2013-40855-R]
- Gobierno de Aragon [E19_20R]
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Proline is found in a cis conformation in proteins more often than other proteinogenic amino acids, where it influences structure and modulates function, being the focus of several high-resolution structural studies. However, until now, technical and methodological limitations have hampered the site-specific investigation of the conformational preferences of prolines present in poly proline (poly-P) homorepeats in their protein context. Here, we apply site-specific isotopic labeling to obtain high-resolution NMR data on the cis/trans equilibrium of prolines within the poly-P repeats of huntingtin exon 1, the causative agent of Huntington's disease. Screening prolines in different positions in long (poly-P-11) and short (poly-P-3) poly-P tracts, we found that, while the first proline of poly-P tracts adopts similar levels of cis conformation as isolated prolines, a length-dependent reduced abundance of cis conformers is observed for terminal prolines. Interestingly, the cis isomer could not be detected in inner prolines, in line with percentages derived from a large database of proline-centered tripeptides extracted from crystallographic structures. These results suggest a strong cooperative effect within poly-Ps that enhances their stiffness by diminishing the stability of the cis conformation. This rigidity is key to rationalizing the protection toward aggregation that the poly-P tract confers to huntingtin. Furthermore, the study provides new avenues to probe the structural properties of poly-P tracts in protein design as scaffolds or nanoscale rulers.
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