Mechanistic study of the human phosphoserine phosphatase (hPSP): crystallographic and computational approaches

Prize: Prize (including medals and awards)

Description

L-Serine is a non-essential amino acid formed using the synthesis from an intermediate of glycolysis. Over the years, the serine pathway was implicated in diverse diseases including psychomotor retardements, severe tetraplegia, microcephaly, neurodegenerative disorders or Williams syndrome. [1, 2] Since the nineties, the serine pathway sparked an interest in the cancer research. The studies highlight a link between the over-activation of this pathway and the cellular proliferation of tumoral cells. [3] On the other hand, the overexpression of human phosphoserine phosphatase (hPSP) has been linked to chemoresistance. [4] In this context, hPSP, a Mg2+-dependent enzyme, is a therapeutic target for the treatment of cancer. However, before this work, the mechanism of hPSP was still mysterious and the crystallographic structures of the enzyme in an active form had never been solved. [5, 6] Nevertheless, a better understanding of this mechanism may help to further in the understanding of the diseases.

In order to elucidate the mechanism of hPSP, the crystallisation of the enzyme with ligands was realised to determine their structures in the catalytic pocket and to highlight the major interactions. The observation of the different active sites with selected ligands led to a new mechanistic hypothesis. Afterwards, a first principles computational approach was used to describe the thermodynamics
and the kinetics properties for each step of the mechanism. By combining the computational and experimental results, the structure-based elucidation of the mechanism has been achieved. [7]

[1] M. Veiga-da Cunha, J. F. Collet, B. Prieur, J. Jaeken, Y. Peeraer, A. Rabbijns, and E. Van Schaftingen. European Journal of Human Genetics,
12(2):163–166, 2004.
[2] L. Tabatabaie, L. W. Klomp, R. Berger, and T. J. de Koning. Molecular Genetics and Metabolism, 99(3):256–262, 2010.
[3] R. J. Deberardinis. Cell Metabolism, 14(3):285–286, 2011.
[4] X. Li, Z. Xun, and Y. Yang. Biochem. Biophys. Res. Commun., 477(4):633–639, 2016.
[5] Y. Peeraer, A. Rabijns, J. F. Collet, E. Van Schaftingen, and C. De Ranter. Eur. J. Biochem., 271(16):3421–3427, 2004.
[6] H. Y. Kim, Y. S. Heo, J. H. Kim, M. H. Park, J. Moon, E. Kim, D. Kwon, J. Yoon, D. Shin, E. june Jeong, S. Yong Park, T. G. Lee, Y. H. Jeon, S. Ro,
J. M. Cho, and K. Y. Hwang. Journal of Biological Chemistry, 277(48):46651–46658, 2002.
[7] M. Haufroid, M. Mirgaux, L. Leherte, and J. Wouters. Acta Crystallographica Section D: Structural Biology, 75(6), 2019.
Degree of recognitionNational

Prize (including medals and awards)

eventSFMBBM graduate school reunion
locationUniversité libre de Bruxelles, Bruxelles, Belgium
Period15 Nov 2019 → 15 Nov 2019