Versatility of SH3 Domains in the Cellular Machinery

Azuaga, Ana I.; Atienza, Salvador Casares

doi:10.1007/978-3-319-20098-9_3

Cited by 1 publication

(3 citation statements)

References 183 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The final model has all residues in the allowed region of the Ramachandran plot. The overall structure reveals a five-stranded antiparallel β-barrel, a characteristic of all known SH3 domains, and three loops (RT, n-Src, and 3 10 helix), commonly involved in the recognition of both proline-rich and nonproline ligands ( 16 – 18 ) ( Fig. 4 B ).…”

Section: Resultsmentioning

confidence: 99%

“…One of the most widely studied protein interaction modules is the Src homology 3 (SH3) 3 domain ( 16 – 18 ). There are ∼300 SH3 domains in the human genome, present in over 200 proteins ( 19 ).…”

Section: Introductionmentioning

confidence: 99%

“…However, several SH3 domains bind noncanonical motifs; for example, the Gads SH3 domain binds SLP-76 via an R XX K motif ( 24 ), the Eps8 SH3 binds e3b1/Abi-1 ( 25 , 26 ) and RN-tre ( 27 , 28 ) via a P XX DY motif ( 29 ), and the Fyn SH3 domain binds SKAP55 via an RK XX Y XX Y motif ( 30 ). Interestingly, structural studies show that most of the noncanonical ligand sequences are recognized by the same molecular surface of the SH3 domains ( 16 , 17 ) that is used for binding proline-rich motifs.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Identification of two distinct peptide-binding pockets in the SH3 domain of human mixed-lineage kinase 3

Kokoszka

Kall

Khosla

et al. 2018

Journal of Biological Chemistry

View full text Add to dashboard Cite

Mixed-lineage kinase 3 (MLK3; also known as MAP3K11) is a Ser/Thr protein kinase widely expressed in normal and cancerous tissues, including brain, lung, liver, heart, and skeletal muscle tissues. Its Src homology 3 (SH3) domain has been implicated in MLK3 autoinhibition and interactions with other proteins, including those from viruses. The MLK3 SH3 domain contains a six-amino-acid insert corresponding to the n-Src insert, suggesting that MLK3 may bind additional peptides. Here, affinity selection of a phage-displayed combinatorial peptide library for MLK3's SH3 domain yielded a 13-mer peptide, designated “MLK3 SH3–interacting peptide” (MIP). Unlike most SH3 domain peptide ligands, MIP contained a single proline. The 1.2-Å crystal structure of the MIP-bound SH3 domain revealed that the peptide adopts a β-hairpin shape, and comparison with a 1.5-Å apo SH3 domain structure disclosed that the n-Src loop in SH3 undergoes an MIP-induced conformational change. A 1.5-Å structure of the MLK3 SH3 domain bound to a canonical proline-rich peptide from hepatitis C virus nonstructural 5A (NS5A) protein revealed that it and MIP bind the SH3 domain at two distinct sites, but biophysical analyses suggested that the two peptides compete with each other for SH3 binding. Moreover, SH3 domains of MLK1 and MLK4, but not MLK2, also bound MIP, suggesting that the MLK1–4 family may be differentially regulated through their SH3 domains. In summary, we have identified two distinct peptide-binding sites in the SH3 domain of MLK3, providing critical insights into mechanisms of ligand binding by the MLK family of kinases.

show abstract

Section: Resultsmentioning

confidence: 99%