5np5
Abl2 SH3 pTyr116/161
Structural highlights
FunctionABL2_HUMAN Non-receptor tyrosine-protein kinase that plays an ABL1-overlapping role in key processes linked to cell growth and survival such as cytoskeleton remodeling in response to extracellular stimuli, cell motility and adhesion and receptor endocytosis. Coordinates actin remodeling through tyrosine phosphorylation of proteins controlling cytoskeleton dynamics like MYH10 (involved in movement); CTTN (involved in signaling); or TUBA1 and TUBB (microtubule subunits). Binds directly F-actin and regulates actin cytoskeletal structure through its F-actin-bundling activity. Involved in the regulation of cell adhesion and motility through phosphorylation of key regulators of these processes such as CRK, CRKL, DOK1 or ARHGAP35. Adhesion-dependent phosphorylation of ARHGAP35 promotes its association with RASA1, resulting in recruitment of ARHGAP35 to the cell periphery where it inhibits RHO. Phosphorylates multiple receptor tyrosine kinases like PDGFRB and other substrates which are involved in endocytosis regulation such as RIN1. In brain, may regulate neurotransmission by phosphorylating proteins at the synapse. ABL2 acts also as a regulator of multiple pathological signaling cascades during infection. Pathogens can highjack ABL2 kinase signaling to reorganize the host actin cytoskeleton for multiple purposes, like facilitating intracellular movement and host cell exit. Finally, functions as its own regulator through autocatalytic activity as well as through phosphorylation of its inhibitor, ABI1.[1] [2] [3] [4] [5] Publication Abstract from PubMedSrc homology 3 (SH3) domains bind proline-rich linear motifs in eukaryotes. By mediating inter- and intramolecular interactions, they regulate the functions of many proteins involved in a wide variety of signal transduction pathways. Phosphorylation at different tyrosine residues in SH3 domains have been reported previously. In several cases, the functional consequences have also been investigated. However, a full understanding of the effects of tyrosine phosphorylation on the ligand interactions and cellular functions of SH3 domains requires detailed structural, atomic-resolution studies along with biochemical and biophysical analyses. Here, we present the first crystal structures of tyrosine-phosphorylated human SH3 domains derived from the Abelson-family kinases ABL1 and ABL2 at 1.6 and 1.4 A resolutions, respectively. The structures revealed that simultaneous phosphorylation of Tyr-89 and Tyr-134 in ABL1, or the homologous residues Tyr-116 and Tyr-161 in ABL2 induce only minor structural perturbations. Instead, the phosphate groups sterically blocked the ligand-binding grooves, thereby strongly inhibiting the interaction with proline-rich peptide ligands. Although some crystal contact surfaces involving phosphotyrosines suggested the possibility of tyrosine-phosphorylation induced dimerization, we excluded this possibility by using small-angle X-ray scattering (SAXS), dynamic light scattering (DLS), and NMR relaxation analyses. Extensive analysis of relevant databases and literature revealed that the residues phosphorylated in our model systems are not only well conserved in other human SH3 domains, but that the corresponding tyrosines are known phosphorylation sites in vivo in many cases. We conclude that tyrosine phosphorylation might be a mechanism involved in the regulation of the human SH3 interactome. Structural insights into the tyrosine phosphorylation-mediated inhibition of SH3 domain-ligand interactions.,Mero B, Radnai L, Gogl G, Toke O, Leveles I, Koprivanacz K, Szeder B, Dulk M, Kudlik G, Vas V, Cserkaszky A, Sipeki S, Nyitray L, Vertessy BG, Buday L J Biol Chem. 2019 Jan 18. pii: RA118.004732. doi: 10.1074/jbc.RA118.004732. PMID:30659095[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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