title: Analogous regulatory sites within the alphaC-beta4 loop regions of ZAP-70 tyrosine kinase and AGC kinases.
abstract: The precise positioning of the flexible C-helix in the catalytic core is a critical step in the activation of most protein kinases. Consequently, the alphaC-beta4 loop, which anchors the C-helix to the catalytic core, is highly conserved and mediates key structural interactions that serve as a hinge for C-helix movement. While these hinge interactions are conserved across diverse eukaryotic protein kinase structures, some families such as AGC kinases diverge from the canonical hinge interactions. This divergence was recently proposed to facilitate an alternative mode of regulation wherein a conserved C-terminal tail interacts with the alphaC-beta4 loop to position the C-helix. Here we show how interactions between the alphaC-beta4 loop and the N-terminal SH2 domain of ZAP-70 tyrosine kinase are mechanistically and functionally analogous to interactions between the alphaC-beta4 loop and the C-terminal tail of AGC kinases. Such cis regulation of protein kinase activity may be a feature of other eukaryotic protein kinase families as well.
authors.affiliation: Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA 92093-0654, USA. kannan@ucsd.edu
authors.forename: Natarajan
authors.initials: N
authors.lastname: Kannan
authors.forename: Andrew F
authors.initials: AF
authors.lastname: Neuwald
authors.forename: Susan S
authors.initials: SS
authors.lastname: Taylor
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D020134:Catalytic Domain; D017868:Cyclic AMP-Dependent Protein Kinases / Q000737:chemistry / Q000378:metabolism; D017869:Cyclic GMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D048369:MAP Kinase Kinase 1 / Q000737:chemistry / Q000378:metabolism; D011493:Protein Kinase C / Q000737:chemistry / Q000378:metabolism; D011494:Protein Kinases / Q000737:chemistry* / Q000378:metabolism*; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D021122:Protein Subunits / Q000737:chemistry / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D000072377:Syk Kinase; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000737:chemistry* / Q000378:metabolism*; D018909:src Homology Domains
chemical_list: D017868:Cyclic AMP-Dependent Protein Kinases; D017869:Cyclic GMP-Dependent Protein Kinases; D047908:Intracellular Signaling Peptides and Proteins; D048369:MAP Kinase Kinase 1; D011493:Protein Kinase C; D011494:Protein Kinases; D021122:Protein Subunits; D011505:Protein-Tyrosine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D000072377:Syk Kinase; D051746:ZAP-70 Protein-Tyrosine Kinase; C000606896:SYK protein, human