Connexins and Pannexins-Similarities and Differences According to the FOD-M Model

Abstract

Connexins and pannexins are the transmembrane proteins of highly distinguished biological activity in the form of transport of molecules and electrical signals. Their common role is to connect the external environment with the cytoplasm of the cell, while connexin is also able to link two cells together allowing the transport from one to another. The analysis presented here aims to identify the similarities and differences between connexin and pannexin. As a comparative criterion, the hydrophobicity distribution in the structure of the discussed proteins was used. The comparative analysis is carried out with the use of a mathematical model, the FOD-M model (fuzzy oil drop model in its Modified version) expressing the specificity of the membrane's external field, which in the case of the discussed proteins is significantly different from the external field for globular proteins in the polar environment of water. The characteristics of the external force field influence the structure of protein allowing the activity in a different environment.

Keywords: connexin; hydrophobicity; membrane proteins; pannexin; transmembrane channel.

Figure 1

The summary of M distributions for connexin in the presence of Ca²⁺ (K = 1.7) and in its absence (K = 1.4)—status of chain A in complexes is shown. The numbers on the x-axis represent the order of residues in a chain—the numbers are not the positions as it is given in PDB.

Figure 2

3D structure of: (A)—connexin’s hemi-channel, (B)—pannexin’s channel with secondary structure distinguished: yellow—Beta-sheet, magenta—transmembrane helices, dark blue—external helices, green—random coil. The beta-sheet is in the outer membrane part that is exposed to the outside of the cell. (C,D) represent the differences in channel construction as well as the six and 7-fold symmetry. (E,F)—hydrophobicity visualization: connexin and pannexin respectively. Images (E,F) created by NGL Viewer: Rose et al. (2018) NGL viewer: web-based molecular graphics for large complexes. Bioinformatics doi:10.1093/bioinformatics/bty419, and RCSB PDB. (A,B)—orientation of the molecules: Top—intra-cellular area, bottom—extra-cellular area; (C,D)—orientation from the point of view of the intra-cellular area—symmetry axis perpendicular to the plane of the figure; (E,F)—side view arbitrarily selected to visualize the shape differences of the compared complexes.

Figure 3

Profiles for the distribution of T (navy), O (pink), and M (turquoise)for K values as shown in the legend: (A)—6L3T—connexin, (B)—7F8J—pannexin.

Figure 4

Profiles for the T (dark blue), O (pink), and M (turquoise) distributions were calculated for single chain (A)—connexin, (B)—pannexin. Blue dots—bottom line—residues interacting with adjacent chains.

Figure 5

Summary of profiles for identification of analogous segments in pannexin (red) and connexin chains (blue) (A)—T; (B)—O; for chains treated as individual structural units pannexin (blue) and connexin (orange) and sections identified as analogous in the structure of single chains—identification based on the T profile. The colors differentiate the fragments as shown also in Figure 6 and Table 2.

Figure 6

3D presentation showing the analogous fragments in the chain treated as individual structural units: (A)—connexin, (B)—pannexin. Colors as given in Table 2 and Figure 5.

Figure 7

Comparison of hydrophobicity profiles: (A)—profile T, (B)—profile O analogical in pannexin (red) and connexin (blue) as observed in the complex and sections identified as analogous in T profiles of complexes. Similar fragments are distinguished by colors according to the presentation in Figure 8 and Table 2.

Figure 8

3D presentation showing the analogous fragments in the complex—(A)—connexin, (B)—pannexin. Colors identification is given in Table 2. Notice the opposite orientation of the selected fragments shown by color arrows. Chain (A)—dark blue. The two white chains in each structure visualize the surrounding of the discussed chain. Molecule orientation:—Top—intra-cellular; Bottom—extracellular direction. Colors as given in Table 2 and Figure 7.

Figure 9

3D presentation: (A)—pannexin; (B)—connexin with highlighted parts: the part facing the cytoplasm—red, the part anchored in the membrane—yellow, the part facing the outside of the cell—blue marine. Violet chains—adjacent chains to visualize the mutual orientation of adjacent chains. This status is given in Table 3.

Figure 10

Examples of distributions: (A)—distribution O (pink) and reference Gaussian distribution T (with parameter $\sigma$) expressing the presence of the central hydrophobic core (dark blue). (B)—the second reference distribution R (light blue) superimposed—expressing a lack of any variation in the hydrophobicity.

Figure 11

(A)—the comparison of plots of distributions M for the three different values of K; (B)—plot of distribution M for a very high value of K (3.0). The distributions T and O are marked in navy blue and pink respectively.

Figure 12

Determining the optimal value of coefficient K. The lowest $D_{\mathit{KL}}$ value is marked (red circle).