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. 2023 Oct 24;13(11):1564.
doi: 10.3390/biom13111564.

Analysis of Structural Changes in the Protein near the Phosphorylation Site

Affiliations

Analysis of Structural Changes in the Protein near the Phosphorylation Site

Kirill S Nikolsky et al. Biomolecules. .

Abstract

Modification of the protein after synthesis (PTM) often affects protein function as supported by numerous studies. However, there is no consensus about the degree of structural protein changes after modification. For phosphorylation of serine, threonine, and tyrosine, which is a common PTM in the biology of living organisms, we consider topical issues related to changes in the geometric parameters of a protein (Rg, RMSD, Cα displacement, SASA). The effect of phosphorylation on protein geometry was studied both for the whole protein and at the local level (i.e., in different neighborhoods of the modification site). Heterogeneity in the degree of protein structural changes after phosphorylation was revealed, which allowed for us to isolate a group of proteins having pronounced local structural changes in the neighborhoods of up to 15 amino acid residues from the modification site. This is a comparative study of protein structural changes in neighborhoods of 3-15 amino acid residues from the modified site. Amino acid phosphorylation in proteins with pronounced local changes caused switching from the inactive functional state to the active one.

Keywords: local change in protein structure; phosphorylation; post-translational modification; three-dimensional protein structure.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The flow diagram of the study includes the following steps: searching for phosphorylated proteins in PDB, selecting protein pairs (the intact and modified forms), performing comparative analysis of protein geometry for each pair, and detecting local changes in protein structure after modification.
Figure 2
Figure 2
(a) The number of proteins in PDB containing non-canonical amino acid residues SEP, TPO, or PTR; (b) Variants of the secondary structure of the protein where the modification site is located; (c) The number of non-canonical amino acids for each protein chain (see Supplementary Table S3).
Figure 3
Figure 3
Distribution histograms of Cα displacement for the structures from groups (a) Group N2 (1E9H chain C—modified form, 2V22 chain C—intact form; 2GQG chain B—modified form, 2G1T chain C—intact form and (b) Group N3 (2XIX chain A—modified form, 3R01 chain A—intact form; 2AK7 chain B—modified form, 1MU4 chain A—intact form). The OX axis corresponds to the number of amino acid residues in the sequence; the OY axis corresponds to the Cα displacement, Å. Green color and arrows indicate the Cα displacement of modified amino acid residues. The regions corresponding to coils (irregular regions of the protein structure) are highlighted in black along the OX axis. Such plots for whole N2 and N3 subsets are available at [44].
Figure 4
Figure 4
Spread of RMSD, Rg, and SASA values for the neighborhoods of the modification site: ±15, ±12, ±9, ±6, and ±3 (nuclear density estimate). The left column shows the data for group N2; the right one, for group N3. Changes in the studied neighborhood of the modification site of RMSD values (a,b); Rg (c,d); and SASA (e,f). The OX axis corresponds to the RMSD (Å), ∆Rg (%), and ∆SASA (Å2) values, respectively. The Y axis shows the number of structures (left) and the distribution density (right). Correspondence of the curve colors to different neighborhoods is shown in the legend: blue—RMSD, assessment of changes in the geometry of the whole protein after modification; brown—RMSD_3, RMSD for the neighborhood ±3; lilac—RMSD_6, RMSD for the neighborhood of ±6; red—RMSD_9, RMSD for the neighborhood of ±9 a; green—RMSD_12, RMSD for the neighborhood ±12; yellow—RMSD_15, RMSD for the neighborhood ±15.
Figure 5
Figure 5
Comparative analysis of the geometric characteristics of the neighborhood of the modification site. The neighborhood of the modification site is plotted along the OX axis: ±15, ±12, ±9, ±6, and ±3. The OS axis corresponds to the values of median RMSD, Å (a); median ∆Rg, % (b); and ∆SASA, Å2 (c). The calculated characteristics for groups N2 and N3 are shown in red and blue, respectively.
Figure 6
Figure 6
A model of superimposed intact protein (green) and PTM form (light blue) designated on (a) proto-oncogene tyrosine-protein kinase Src (PDB ID 1YI6), 416PTR; 416PTR, and (b) cyclin-dependent kinase 2 (PDB ID 1E9H), 160TPO.

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