Database Accession: DI1020007
Name: EspFu-R47 domain bound to IRTKS-SH3 domain
PDB ID: 2kxc
Experimental method: NMR
Source organism: Escherichia coli O157:H7 / Homo sapiens
Proof of disorder:
Kd: 5.00×10-07 M
Primary publication of the structure:
Aitio O, Hellman M, Kazlauskas A, Vingadassalom DF, Leong JM, Saksela K, Permi P
Recognition of tandem PxxP motifs as a unique Src homology 3-binding mode triggers pathogen-driven actin assembly.
(2010) Proc. Natl. Acad. Sci. U.S.A. 107: 21743-8
PMID: 21098279
Abstract:
Src homology 3 (SH3) domains are globular protein interaction modules that regulate cell behavior. The classic SH3 ligand-binding site accommodates a hydrophobic PxxP motif and a positively charged specificity-determining residue. We have determined the NMR structure of insulin receptor tyrosine kinase substrate (IRTKS) SH3 domain in complex with a repeat from Escherichia coli-secreted protein F-like protein encoded on prophage U (EspF(U)), a translocated effector of enterohemorrhagic E. coli that commandeers the mammalian actin assembly machinery. EspF(U)-IRTKS interaction is among the highest affinity natural SH3 ligands. Our complex structure reveals a unique type of SH3 interaction based on recognition of tandem PxxP motifs in the ligand. Strikingly, the specificity pocket of IRTKS SH3 has evolved to accommodate a polyproline type II helical peptide analogously to docking of the canonical PxxP by the conserved IRTKS SH3 proline-binding pockets. This cooperative binding explains the high-affinity SH3 interaction and is required for EspF(U)-IRTKS interaction in mammalian cells as well as the formation of localized actin "pedestals" beneath bound bacteria. Importantly, tandem PxxP motifs are also found in mammalian ligands and have been shown to contribute to IRTKS SH3 recognition similarly.
Annotations from the GeneOntology database. Only terms that fit at least two of the interacting proteins are shown.Molecular function: not assigned
Biological process: not assigned
Cellular component: not assigned
Structural annotations of the participating protein chains.Entry contents: 2 distinct polypeptide molecules
Chains: B, A
Notes: No modifications of the original PDB file.
Name: Secreted effector protein EspF(U)
Source organism: Escherichia coli O157:H7
Length: 48 residues
Sequence:Sequence according to PDB SEQRESGLPDVAQRLMQHLAEHGIQPARNMAEHIPPAPNWPAPTPPVQNEQSRP
UniProtKB AC: P0DJ89 (positions: 220-267) Coverage: 14.2%
UniRef90 AC: UniRef90_P0DJ88 (positions: 221-267)
Name: Brain-specific angiogenesis inhibitor 1-associated protein 2-like protein 1
Source organism: Homo sapiens
Length: 67 residues
Sequence:Sequence according to PDB SEQRESGSHMKKQKVKTIFPHTAGSNKTLLSFAQGDVITLLIPEEKDGWLYGEHDVSKARGWFPSSYTKLLEE
UniProtKB AC: Q9UHR4 (positions: 336-402) Coverage: 13.1%
UniRef90 AC: UniRef90_Q9UHR4 (positions: 339-402)
Evidence demonstrating that the participating proteins are unstructured prior to the interaction and their folding is coupled to binding. Chain B:
The 221-314 region described in IDEAL entry IID90008 covers 98% of the sequence present in the structure. The protein region involved in the interaction contains tandem PxxP SH3-binding motifs (PMID: 21098279).
Chain A:
The SH3 domain involved in the interaction is known to adopt a stable structure in isolation (see Pfam domain PF14604). A solved monomeric structure of the domain from a homologous protein is represented by PDB ID 1ark.
Structures from the PDB that contain the same number of proteins, and the proteins from the two structures show a sufficient degree of pairwise similarity, i.e. they belong to the same UniRef90 cluster (the full proteins exhibit at least 90% sequence identity) and convey roughly the same region to their respective interactions (the two regions from the two proteins share a minimum of 70% overlap). The structure can be rotated by left click and hold anywhere on the structure. Representation options can be edited by right clicking on the structure window.
