Short Linear Motifs recognized by SH2, SH3 and Ser/Thr Kinase domains are conserved in disordered protein regions

Abstract

Background: Protein interactions are essential for most cellular functions. Interactions mediated by domains that appear in a large number of proteins are of particular interest since they are expected to have an impact on diversities of cellular processes such as signal transduction and immune response. Many well represented domains recognize and bind to primary sequences less than 10 amino acids in length called Short Linear Motifs (SLiMs).

Results: In this study, we systematically studied the evolutionary conservation of SLiMs recognized by SH2, SH3 and Ser/Thr Kinase domains in both ordered and disordered protein regions. Disordered protein regions are protein sequences that lack a fixed three-dimensional structure under putatively native conditions. We find that, in all these domains examined, SLiMs are more conserved in disordered regions. This trend is more evident in those protein functional groups that are frequently reported to interact with specific domains.

Conclusion: The correlation between SLiM conservation with disorder prediction demonstrates that functional SLiMs recognized by each domain occur more often in disordered as compared to structured regions of proteins.

Figure 1

Relative conservation of SLiMs. (A) Low relative conservation of conserved SLiM in overall conserved protein. Schematic illustration (left panel) and alignment (right panel) around Y54 of Histone H3.1. (B) High relative conservation of conserved SLiM in overall less conserved protein. Schematic illustration of relative conservation (left panel) and alignment (right panel) around Y631 of IL4R.

Figure 2

Conservation score and SH2 selectivity values of Tyr-SLiMs in disordered and ordered protein regions in 11 most studied RTKs. (A) SH2 binding Tyr-SLiMs are significantly more conserved than those that do not bind to SH2 domains in both order and disorder groups (both p < 0.001, Mann-Whitney test). (B) Percentage of SLiMs that reported to interact with SH2 domains.

Figure 3

Schematic of the comparion among conservation profiles of SLiMs. For a particular domain that are under study, proteins are first grouped according to their molecular functions then further grouped into three categories according to the involvement of interaction with that domain (frequent, occasional or rare). In each of the categories obtained from the last step, proteins sequences are sorted into ordered and disordered regions. We then get the SLiMs in the protein regions and further grouped them into low, lower medium, upper medium and high domain selectivities. Conservation profiles are calculated for SLiMs in each group. The final output is the difference of ln(C_R) value between SLiM that with medium, upper medium and high selectivity value and that with low selectivity value.

Figure 4

Conservation profiles of Short Linear Motifs (SLiM). Conservation profiles of SLiMs with lower medium, upper medium and high selectivity values for SH2, SH3 and S/T Kinase domains in functional groups that are frequent, occasional or rare interaction partners of each domain.