5k28
Structure of the unbound SH3 domain of MLK3
Structural highlights
FunctionM3K11_HUMAN Activates the JUN N-terminal pathway. Required for serum-stimulated cell proliferation and for mitogen and cytokine activation of MAPK14 (p38), MAPK3 (ERK) and MAPK8 (JNK1) through phosphorylation and activation of MAP2K4/MKK4 and MAP2K7/MKK7. Plays a role in mitogen-stimulated phosphorylation and activation of BRAF, but does not phosphorylate BRAF directly. Influences microtubule organization during the cell cycle.[1] [2] [3] [4] Publication Abstract from PubMedMixed-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-A crystal structure of the MIP-bound SH3 domain revealed that the peptide adopts a beta-hairpin shape, and comparison with a 1.5-A apo SH3 domain structure disclosed that the n-Src loop in SH3 undergoes an MIP-induced conformational change. A 1.5-A 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. Identification of two distinct peptide-binding pockets in the SH3 domain of human mixed-lineage kinase 3.,Kokoszka ME, Kall SL, Khosla S, McGinnis JE, Lavie A, Kay BK J Biol Chem. 2018 Aug 31;293(35):13553-13565. doi: 10.1074/jbc.RA117.000262. Epub, 2018 Jul 6. PMID:29980598[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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