The Eukaryotic Linear Motif resource for
Functional Sites in Proteins
Accession:
Functional site class:
AGC Kinase docking motif
Functional site description:
The AGC kinases constitute a large family of serine/threonine protein kinases consisting of 60 members, including the cAMP- and cGMP-dependent protein kinases (PKA and PKG), the protein kinase C family (PKC), PKB/Akt, ribosomal protein S6 kinases, and the 3-phosphoinositide-dependent protein kinase (PDK1). They regulate many critical processes including metabolism and cell proliferation. Members of this family contain a hydrophobic surface in the N-terminal lobe of their catalytic domain, called the PDK1 Interacting Fragment (PIF) pocket, and a non-catalytic C-terminal tail containing different motifs, including the AGCK docking motif that interacts with the PIF pocket. Both these regions are conserved in Eukaryotic AGC kinases, except for PDK1, which lacks the C-tail. The AGCK docking motif mediates intramolecular interactions to the PIF pocket, serving as a cis-activating module, but can also act as a PDK1 docking site that trans-activates PDK1, which in turn will phosphorylate the docked AGC kinase.
ELMs with same func. site: DOC_AGCK_PIF_1  DOC_AGCK_PIF_2  DOC_AGCK_PIF_3 
ELM Description:
The AGCK docking motif of some AGC kinases, including atypical PKC isoforms and PKC-like kinases (PKN), contains an acidic aspartate or glutamate residue at the position of the phosphorylatable serine/threonine residue present in the DOC_AGCK_PIF_1 motif variant. This acidic residue is flanked by an aromatic residue on either side. The residue directly upstream is most frequently phenylalanine but possibly other aromatic amino acids are allowed, while the residue downstream is either a phenylalanine or a tyrosine. An additional aromatic residue four residues upstream of the acidic residue is invariantly a phenylalanine. The 24-amino acid peptide PIFtide is derived from the AGCK docking motif of the PKN2 kinase and shows a higher affinity to PDK1 than any other PIF binding motif tested so far. In addition, PIFtide has been shown to be capable to activate both PKB and PDK1 with high potency.
Pattern: F..[FWY][DE][FY]
Pattern Probability: 0.0000033
Present in taxon: Eukaryota
Interaction Domain:
Pkinase (PF00069) Protein kinase domain (Stochiometry: 1 : 1)
o See 5 Instances for DOC_AGCK_PIF_2
o Abstract
This entry covers an auto-activating linear motif of AGC group kinases. Several variants of the motif exist, and for many kinases, the motif has been shown to operate in trans to bind and activate the upstream activating kinase PDK1. To make matters more complicated, some variants are regulated by phosphorylation.
The AGC kinases regulate critical processes including metabolism, cell growth, proliferation, survival and differentiation, hence deregulation of these enzymes is a causative factor in different diseases such as cancer and diabetes. Solved structures of AGC kinases show the typical bilobal kinase fold of the kinase domain, consisting of a small N-terminal lobe (N-lobe) and a larger C-terminal lobe (C-lobe). Regulation of kinase activity is mainly achieved through phosphorylation of the activation or T-loop, located in the C-lobe and connected to the N-lobe through the alpha-C helix. This modification results in conformational changes, mainly in the alpha-C helix, that reposition key catalytic and substrate binding residues. Sandwiched between the N- and C-lobe is an ATP-binding site that provides the phosphate-donor during phosphorylation. Repositioning of the alpha-C helix upon kinase activation allows formation of a salt bridge between an alpha-C helix glutamate and a conserved lysine residue within the beta-3 strand that interacts with the alpha and beta phosphates of ATP (Pearce,2010).
The non-catalytic C-terminal tail of the kinase is also involved in repositioning of the alpha-C helix. The alpha-C helix is part of a hydrophobic pocket and an adjacent phosphate-binding site in the N-lobe, called the PIF pocket, which interacts with the AGCK docking motif (PDK1 Interacting Fragment (PIF) / hydrophobic motif (HM)) that is present in the C-tail of AGC kinases. This interaction stabilizes the active conformation of the alpha-C helix through an allosteric mechanism. Both the PIF pocket and the C-terminal region are conserved in Eukaryotic AGC kinases, except for PDK1, which lacks the C-terminal part. The AGCK docking motif mediates intramolecular interactions to the PIF pocket, serving as a cis-activating module, together with other regulatory sequences present in the C-tail of the kinase. However, in some kinases it also serves as a PDK1 docking site that trans-activates PDK1, which itself does not possess this regulatory region. Activated PDK1 in turn will phosphorylate and activate the docked AGC kinase (Mora,2004).
Several AGC kinases are involved in mediating signaling downstream of phosphatidyl-inositol-4,5-bisphosphate 3-kinase (PI3K) in response to a wide range of stimuli such as growth factors and hormones. PDK1 functions as a common upstream activator by phosphorylating the other AGC kinases at their activation loop. The PDK1 PIF pocket serves both as an allosteric regulatory site for PDK1 activity and as a docking site for the AGC kinases it phosphorylates, by binding to the AGCK docking motif that is present in the C-tail of its substrates. AGC kinases in their inactive state have an incompatible PIF pocket due to the alpha-C helix being disordered, meaning that their AGCK docking motif is available for binding to the PIF pocket of PDK1, which becomes trans-activated. After being phosphorylated by PDK1, the AGCK docking motif can engage in an intramolecular interaction with its functional PIF pocket, resulting in release from PDK1 and full activation of the kinase.
The AGCK docking motif generally appears as three aromatic residues, most often phenylalanines, surrounding a phosphorylatable serine or threonine residue (DOC_AGCK_PIF_1). Phosphorylation of this serine/threonine increases the affinity of the motif for the PIF pocket, which allows fine-tuning the cis and trans interactions of the motif. The mechanisms and kinases involved in phosphorylation of the AGCK docking motif differ for the different kinases. Some alternative patterns of the motif exist. In atypical PKC forms and PKC-like (PKN) kinases, the phosphorylatable serine or threonine residue is replaced by an acidic phosphomimetic aspartate or glutamate residue (DOC_AGCK_PIF_2). In other AGC kinases, including PKA, the motif is located at the very C-terminal and contains only the first two core aromatic residues (DOC_AGCK_PIF_3). In many cases, full activation of the AGC kinases is also dependent on additional signals that are specific for each kinase and that provide spatial and conformational regulation.
o 12 selected references:

o 7 GO-Terms:

o 5 Instances for DOC_AGCK_PIF_2
(click table headers for sorting; Notes column: =Number of Switches, =Number of Interactions)
Acc., Gene-, NameStartEndSubsequenceLogic#Ev.OrganismNotes
Q16513 PKN2
PKN2_HUMAN
974 979 ILSEEEQEMFRDFDYIADWC TP 13 Homo sapiens (Human)
1 
Q16512 PKN1
PKN1_HUMAN
932 937 PLTAAEQAAFLDFDFVAGGC TP 4 Homo sapiens (Human)
1 
Q02956 Prkcz
KPCZ_MOUSE
575 580 KRIDQSEFEGFEYINPLLLS TP 4 Mus musculus (House mouse)
1 
Q05513 PRKCZ
KPCZ_HUMAN
575 580 KRIDQSEFEGFEYINPLLLS TP 4 Homo sapiens (Human)
1 
P41743 PRKCI
KPCI_HUMAN
579 584 RKIDQSEFEGFEYINPLLMS TP 4 Homo sapiens (Human)
1 
Please cite: ELM 2016-data update and new functionality of the eukaryotic linear motif resource. (PMID:26615199)

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