Exploration of the conformational space of SERF1a
Résumé
Intrinsically disordered proteins (IDP) and intrinsically disordered regions (IDR) are at the center of numerous regulation and control pathways in the cell, and attract consequently extreme interest nowadays in structural biology. The optimization problem that arises for protein structure determination is more complex for such objects as the convergence criterion is more difficult to set up and the size of the conformational space is a obstacle to exhaustive exploration. The threading-augmented interval Branch-and-Prune (TAiBP), based on a reformulating of the Distance Geometry Problem (DGP), provides a theoretical frame for the fast generation of protein conformations (Malliavin et al, 2019;
Malliavin, 2021). Combinatorial explosion of the Branch-and-Prune approach due to exponential complexity is alleviated by partitioning the input instances into consecutive peptide fragments and by systematic solutions clustering. A pipeline is proposed to exhaustively sample protein conformations with TAiBP using backbone angle limits obtained by nuclear magnetic resonance (NMR), and to determine the populations of conformations by fitting small angle X-ray scattering (SAXS) data or Ramachandran probability maps (Förster et al, 2022).
The approach TAiBP is applied here to the protein SERF1a, a 62-residue IDP, playing an important role into the fibrillation of alpha synuclein (Pras et al, 2021). Basing on the NMR chemical shifts measured on SERF1a at two pH values, predictions of Ramachandran regions using TALOS-N and delta2D were used to generate sets of conformations, corresponding to various levels of stability of alpha helices experimentally observed. These conformations were then filtered as described above. Slightly smaller radii of gyration are observed for filtered conformations at pH 6, which agrees with the observation of a long-range NOE at this pH values. In addition, the filtered conformations permits to detect propensity for the residues to form druggable interaction pockets. These pockets provide starting points to influence the interaction of SERF1a with its interaction partners during the fibrillation of alpha synuclein.
References:
D. Forster, J. Idier, L. Liberti, A. Mucherino, J. H. Lin, and T. E. Malliavin. Low-resolution description of the conformational space for intrinsically disordered proteins. Sci Rep, 12:19057, 2022.
T. E. Malliavin. Tandem domain structure determination based on a systematic enumeration of conformations. Sci Rep, 11:16925, 2021.
T. E. Malliavin, A. Mucherino, C. Lavor, and L. Liberti. Systematic Exploration of Protein Conformational Space Using a Distance Geometry Approach. J Chem Inf Model, 59:4486-4503, 2019.
A. Pras, B. Houben, F. A. Aprile, R. Seinstra, R. Gallardo, L. Janssen, W. Hogewerf, C. Gallrein, M. De Vleeschouwer, A. Mata-Cabana, M. Koopman, E. Stroo, M. de Vries, S. Louise Edwards, J. Kirstein, M. Vendruscolo, S. F. Falsone, F. Rousseau, J. Schymkowitz, and E. A. A. Nollen. The cellular modifier MOAG4/SERF drives amyloid formation through charge complementation. EMBO J, 40:e107568, 2021.
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