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Evidence of the reduced abundance of proline cis conformation in protein poly-proline tracts

Abstract : 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) homo-repeats 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 form 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 rationalize the protection towards 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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https://hal.laas.fr/hal-02545935
Contributor : Juan Cortés <>
Submitted on : Friday, April 17, 2020 - 3:19:19 PM
Last modification on : Wednesday, July 8, 2020 - 8:14:10 AM

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Annika Urbanek, Matija Popovic, Carlos Elena-Real, Anna Morató, Alejandro Estaña, et al.. Evidence of the reduced abundance of proline cis conformation in protein poly-proline tracts. Journal of the American Chemical Society, American Chemical Society, 2020, 142 (17), pp.7976-7986. ⟨10.1021/jacs.0c02263⟩. ⟨hal-02545935⟩

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