Disordered Motifs and Domains in Cell Control - October 11-15, 2014

Disordered Motifs and Domains in Cell Control

Monday Speaker Abstracts

Use of Host-like Peptide Motifs in Viral Proteins Is a Prevalent Strategy in Host-Virus Interactions M. Madan Babu . MRC Lab of Molecular Biology, Cambridge, United Kingdom. Viruses interact extensively with host proteins, but the mechanisms controlling these interactions are not well understood. We present a comprehensive analysis of eukaryotic linear motifs (ELMs) in 2,208 viral genomes and reveal that viruses exploit molecular mimicry of host-like ELMs to possibly assist in host-virus interactions. Using a statistical genomics approach, we identify a large number of potentially functional ELMs and observe that the occurrence of ELMs is often evolutionarily conserved but not uniform across virus families. Some viral proteins contain multiple types of ELMs, in striking similarity to complex regulatory modules in host proteins, suggesting that ELMs may act combinatorially to assist viral replication. Furthermore, a simple evolutionary model suggests that the inherent structural simplicity of ELMs often enables them to tolerate mutations and evolve quickly. Our findings suggest that ELMs may allow fast rewiring of host-virus interactions, which likely assists rapid viral evolution and adaptation to diverse environments. Phage display is a powerful technique for specificity profiling of peptide-binding domains. Using highly diverse combinatorial peptide phage libraries, the method is suited for the identification of high affinity ligands with inhibitor potential. A complementary but considerably less explored approach is the proteomic peptide phage display where expression products from exquisitely designed oligonucleotide libraries are displayed on phage particles. Proteomic phage display can be used to uncover protein-protein interactions of potential relevance for cell function. The method is particularly suited for the discovery of interactions between peptide binding domains and their target motifs We recently generated phage libraries displaying all human C-terminal sequences using custom oligonucleotide microarrays and used them to interrogate interactions of human protein-95/disks large/zonula occludens-1 (PDZ) domains. We successfully identified novel PDZ domain interactions of potential relevance to cellular signaling pathways and validated a subset of interactions with a high success rate. I will present our recent results on how the combination of combinatorial and proteomic peptide phage display can be used to elucidate preferences of peptide binding domains and to identify targets of biological relevance. Reference Ivarsson, Y., Arnold, R., McLaughlin, M., Nim, S., Joshi, R., Ray, D., Liu, B., Teyra, J., Pawson, T., Moffat, J., Li, S., Sidhu, S. S., & Sidhu, S. S. Large-scale interaction profiling of PDZ domains through proteomic peptide-phage display using human and viral phage peptidomes. (2014) Proc Natl Acad Sci U S A 111, 2542-2547. Interaction Profiling Using Phage Peptidomes Ylva Ivarsson . Uppsala University, Uppsala, Sweden.

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