The conservation pattern of short linear motifs is highly correlated with the function of interacting protein domains

Siyuan Ren,Yixue Li,Youyu He,Yiguo Wang,Guang Yang,Zhengjun Chen

doi:10.1186/1471-2164-9-452

Abstract

BackgroundMany well-represented domains recognize primary sequences usually less than 10 amino acids in length, called Short Linear Motifs (SLiMs). Accurate prediction of SLiMs has been difficult because they are short (often < 10 amino acids) and highly degenerate. In this study, we combined scoring matrixes derived from peptide library and conservation analysis to identify protein classes enriched of functional SLiMs recognized by SH2, SH3, PDZ and S/T kinase domains.ResultsOur combined approach revealed that SLiMs are highly conserved in proteins from functional classes that are known to interact with a specific domain, but that they are not conserved in most other protein groups. We found that SLiMs recognized by SH2 domains were highly conserved in receptor kinases/phosphatases, adaptor molecules, and tyrosine kinases/phosphatases, that SLiMs recognized by SH3 domains were highly conserved in cytoskeletal and cytoskeletal-associated proteins, that SLiMs recognized by PDZ domains were highly conserved in membrane proteins such as channels and receptors, and that SLiMs recognized by S/T kinase domains were highly conserved in adaptor molecules, S/T kinases/phosphatases, and proteins involved in transcription or cell cycle control. We studied Tyr-SLiMs recognized by SH2 domains in more detail, and found that SH2-recognized Tyr-SLiMs on the cytoplasmic side of membrane proteins are more highly conserved than those on the extra-cellular side. Also, we found that SH2-recognized Tyr-SLiMs that are associated with SH3 motifs and a tyrosine kinase phosphorylation motif are more highly conserved.ConclusionThe interactome of protein domains is reflected by the evolutionary conservation of SLiMs recognized by these domains. Combining scoring matrixes derived from peptide libraries and conservation analysis, we would be able to find those protein groups that are more likely to interact with specific domains.

Highlights

Many well-represented domains recognize primary sequences usually less than 10 amino acids in length, called Short Linear Motifs (SLiMs)
Global Conservation Analysis of SLiMs Recognized by SH2, SH3, PDZ and S/T Kinase Domains Using the PLC-γ1 N-terminal SH2 domain as a model to study the relationship between conservation and function of SLiMs, we found that Tyr-SLiMs predicted to bind to the PLC-γ1 N-terminal SH2 domain have significantly higher ln(CR) scores, compared to TyrSLiMs in PLC-γ1 binding proteins (Mann-Whitney test, p = 0.001; Fig. 3A, left panel, III) and receptor kinase/phosphatase proteins (p = 0.002; Fig. 3A, left panel, II) not predicted to bind to the N-terminal SH2 domain
Taking into consideration all binding partners, we found that for 20 of the 21 SH2 motifs, Tyr-SLiMs recognized by SH2 domains have a higher average ln(CR) score than those not recognized by SH2 domains; 11 of these are statistically significant (p < 0.05)

Summary

Introduction

Many well-represented domains recognize primary sequences usually less than 10 amino acids in length, called Short Linear Motifs (SLiMs). Selective protein-protein interactions are important for cellular functions and are often mediated by protein domains that recognize specific primary sequences within target proteins called Short Linear Motifs (SLiMs). Motifs discovered through polypeptide library screening have shown high levels of agreement with reported domain interaction sites [1,2]. This became the basis for Scansite [3,4], a bioinformatics program developed to predict SLiMs in query proteins that are recognized by specific protein domains. Like those available in Minimotif-Miner [5], QuasiMotifFinder [6], MCS [7] and a treebased scoring [8] applied evolutionary conservation as well as other sequence filters to assess the functional relevance of a hit

Methods

Results

Discussion

Conclusion