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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.

Evidence of the Reduced Abundance of Proline cis Conformation in Protein Poly Proline Tracts