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. 2024 May 12;46(5):4609-4629.
doi: 10.3390/cimb46050280.

In Silico Analysis of Protein-Protein Interactions of Putative Endoplasmic Reticulum Metallopeptidase 1 in Schizosaccharomyces pombe

Dalia González-Esparragoza  1   2 , Alan Carrasco-Carballo  2   3 , Nora H Rosas-Murrieta  1 , Lourdes Millán-Pérez Peña  1 , Felix Luna  4 , Irma Herrera-Camacho  1
Affiliations

In Silico Analysis of Protein-Protein Interactions of Putative Endoplasmic Reticulum Metallopeptidase 1 in Schizosaccharomyces pombe

Dalia González-Esparragoza et al. Curr Issues Mol Biol. .

Abstract

Ermp1 is a putative metalloprotease from Schizosaccharomyces pombe and a member of the Fxna peptidases. Although their function is unknown, orthologous proteins from rats and humans have been associated with the maturation of ovarian follicles and increased ER stress. This study focuses on proposing the first prediction of PPI by comparison of the interologues between humans and yeasts, as well as the molecular docking and dynamics of the M28 domain of Ermp1 with possible target proteins. As results, 45 proteins are proposed that could interact with the metalloprotease. Most of these proteins are related to the transport of Ca2+ and the metabolism of amino acids and proteins. Docking and molecular dynamics suggest that the M28 domain of Ermp1 could hydrolyze leucine and methionine residues of Amk2, Ypt5 and Pex12. These results could support future experimental investigations of other Fxna peptidases, such as human ERMP1.

Keywords: Ermp1; S. pombe; metalloprotease; molecular docking; molecular dynamic; protein–protein interaction.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
PPI network for human ERMP1. Information obtained from the BioGRID database. The network was edited using Cytoscape 3.10 software.
Figure 2
Figure 2
Prediction of a PPI network for Ermp1 in S. pombe. The network was edited using Cytoscape 3.10 software.
Figure 3
Figure 3
Clustering of Ermp1-interacting proteins in S. pombe: (A) Go cellular component and (B) biological process annotation.
Figure 4
Figure 4
Sequence alignment of the M28 domain of Ermp1 in humans and S. pombe.
Figure 5
Figure 5
Three-dimensional structure of the M28 domain of Ermp1 from S. pombe. (A) Homology modeling in Phyre2. Binding site Zn2+ shown in orange. (B) Model validation using the PROCHECK-SAVES v6.0 server. Ramachandran plot shows 85.4% residues are in the most favored region. Editing of the model performed in UCSF Chimera 1.17.1.
Figure 6
Figure 6
Representation of the catalytic cavity of the M28 domain of Ermp1 from S. pombe. (A) Surface model and (B) residues comprising the catalytic cavity. The gray dots represent the coordination bonds between residues with Zn2+. Editing of the model performed in Maestro 13.0.
Figure 7
Figure 7
Molecular docking of the M28 domain of Ermp1 with protein targets (A–F). Highlighted are the binding sites for Zn2+ in orange, the catalytic site in purple, and the catalytic stabilizer in magenta. Additionally, the predicted phosphorylation sites are indicated in cyan. The hydrophobic areas are indicated by the yellow sites, and the ligand cleavage site is represented by the blue segment. The cleavage points are indicated by the pink residues. Solvation was performed using the WaterMap tool, and the models were edited in Maestro 13.0.
Figure 8
Figure 8
Molecular dynamics simulation. Variation in the root mean square deviation (RMSD) of the Ermp1–Pex12, Ermp1–Amk2 and Ermp1–Ypt5 complexes. Each simulation was 120 ns long in the Desmond Molecular Dynamics System to assess the stability of the protein–protein interactions.
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