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This work was supported by the European Research Council under the European Union's H2020 Framework Programme (2014-2020)/ERC Grant Agreement No. [648030], Labex EpiGenMed, an Investissements d'avenir program (ANR-10LABX-12-01) awarded to P.B., and the GPCteR (ANR-17CE11-0022-01) to N.S. The CBS is a member of FranceBioImaging (FBI) and the French Infrastructure for Integrated Structural Biology (FRISBI), two national infrastructures supported by the French National Research Agency (ANR10-INBS-04-01 and ANR-10-INBS-05, respectively). Financial support from the TGIR-RMN-THC Fr3050 CNRS, the Spanish MINECO (CTQ2013-40855-R), and Gobierno de Aragon (research group Aminoa ' cidos y Pe ' ptidos E19_20R) for conducting the research is gratefully acknowledged.

Analysis of institutional authors

Popovic, MatijaAuthor

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April 20, 2022
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Evidence of the Reduced Abundance of Proline cis Conformation in Protein Poly Proline Tracts

Publicated to:Journal Of The American Chemical Society. 142 (17): 7976-7986 - 2020-04-29 142(17), DOI: 10.1021/jacs.0c02263

Authors: Urbanek, A; Popovic, M; Elena-Real, CA; Morato, A; Estana, A; Fournet, A; Allemand, F; Gil, AM; Cativiela, C; Cortes, J; Jimenez, AI; Sibille, N; Bernado, P

Affiliations

Univ Montpellier 29, Ctr Biochim Struct CBS, CNRS, INSERM, 29 Rue Navacelles, Montpellier 34090, France - Author
Univ Toulouse, CNRS, LAAS, Toulouse 31400, France - Author
Univ Zaragoza, Inst Stesis Quim & Catalisis Homogenea ISQCH, Dept Quim Organ, CSIC, Zaragoza 50009, Spain - Author

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) 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.

Keywords

AggregationEvolutionHomorepeatsN-terminusPeptide-bondsPolyprolineResiduesSecondary structureSiteTrans isomerization

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal JOURNAL OF THE AMERICAN CHEMICAL SOCIETY due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2020, it was in position 15/178, thus managing to position itself as a Q1 (Primer Cuartil), in the category Chemistry, Multidisciplinary. Notably, the journal is positioned above the 90th percentile.

Independientemente del impacto esperado determinado por el canal de difusión, es importante destacar el impacto real observado de la propia aportación.

Según las diferentes agencias de indexación, el número de citas acumuladas por esta publicación hasta la fecha 2025-08-02:

  • WoS: 7

Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2025-08-02:

  • The use, from an academic perspective evidenced by the Altmetric agency indicator referring to aggregations made by the personal bibliographic manager Mendeley, gives us a total of: 67.
  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 67 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

  • The Total Score from Altmetric: 4.
  • The number of mentions on the social network X (formerly Twitter): 7 (Altmetric).

It is essential to present evidence supporting full alignment with institutional principles and guidelines on Open Science and the Conservation and Dissemination of Intellectual Heritage. A clear example of this is:

  • The work has been submitted to a journal whose editorial policy allows open Open Access publication.

Leadership analysis of institutional authors

This work has been carried out with international collaboration, specifically with researchers from: France.