How Do Protein Kinases Take a Selfie (Autophosphorylate)?

A profound step in the activation of eukaryotic protein kinases (EPKs) is self-activation by autophosphorylation of their activation loop. This autophosphorylation is believed now to be shared by almost all EPKs. Activation-loop phosphorylation induces conversion from an inactive to an active conformation. Intriguingly, EPKs catalyze this reaction when not in their active state. The autophosphorylation reaction must share structural features with the substrate phosphorylation reaction. It is not clear how it utilizes the ATP-binding and catalytic sites. The prone-to-autophosphorylate conformation is stabilized allosterically by dimerization or via association with auxiliary proteins. The dimers’ organization and the reaction mechanism (cis or trans) are kinase specific. In mitogen-activated protein kinases (MAPKs), autophosphorylation regulation is very tight and occurs via unique mechanisms and structural motifs, specific to each MAPK. Eukaryotic protein kinases (EPKs) control most biological processes and play central roles in many human diseases. To become catalytically active, EPKs undergo conversion from an inactive to an active conformation, an event that depends upon phosphorylation of their activation loop. Intriguingly, EPKs can use their own catalytic activity to achieve this critical phosphorylation. In other words, paradoxically, EPKs catalyze autophosphorylation when supposedly in their inactive state. This indicates the existence of another important conformation that specifically permits autophosphorylation at the activation loop, which in turn imposes adoption of the active conformation. This can be considered a prone-to-autophosphorylate conformation. Recent findings suggest that in prone-to-autophosphorylate conformations catalytic motifs are aligned allosterically, by dimerization or by regulators, and support autophosphorylation in cis or trans. Eukaryotic protein kinases (EPKs) control most biological processes and play central roles in many human diseases. To become catalytically active, EPKs undergo conversion from an inactive to an active conformation, an event that depends upon phosphorylation of their activation loop. Intriguingly, EPKs can use their own catalytic activity to achieve this critical phosphorylation. In other words, paradoxically, EPKs catalyze autophosphorylation when supposedly in their inactive state. This indicates the existence of another important conformation that specifically permits autophosphorylation at the activation loop, which in turn imposes adoption of the active conformation. This can be considered a prone-to-autophosphorylate conformation. Recent findings suggest that in prone-to-autophosphorylate conformations catalytic motifs are aligned allosterically, by dimerization or by regulators, and support autophosphorylation in cis or trans. a key regulatory phosphorylation site found in most eukaryotic protein kinases (EPKs) within a region termed the activation loop. Activation-loop phosphorylation has a crucial role in stabilizing the active conformation of many protein kinases and is considered a biochemical marker for activity. Depending on the EPK, the activation-loop site can be phosphorylated either by autophosphorylation, by a regulating upstream kinase, or by both mechanisms. phosphotransfer activity of eukaryotic protein kinases (EPKs), in which the receiving residue resides within the catalyzing EPK itself or within another twin molecule. Autophosphorylation can be an intermolecular (trans) or an intramolecular (cis) reaction. a family of enzymes that catalyze phosphotransfer of the γ-phosphate group of ATP to serine, threonine, or tyrosine residues of target proteins (substrates). EPKs share 12 conserved subdomains and a conserved 3D fold of the catalytic core, termed the kinase domain. Most EPKs contain additional domains or structural elements, tethered to the kinase domain, which have important roles in their functionality. a eukaryotic protein kinase engineered to lack catalytic activity but to maintain the overall canonical fold of the kinase domain. This is achieved by mutagenesis of key sites that serve for the phosphotransfer reaction. the complement of protein kinases encoded by a genome of an organism. The human kinome, for example, is composed of 518 eukaryotic protein kinases. The kinome can be cataloged into subgroups based on features found within or outside the kinase domain. traditionally defined as a eukaryotic protein kinase that naturally lacks at least one of the functional elements that enable catalytic activity. Recent experimental evidence has shown in a number of cases, for example, the predicted pseudokinases WNK and kinase suppressor of Ras, that kinases missing some canonical catalytic residues do manifest some activity. some eukaryotic protein kinases (EPKs) have been developed in evolution to function as activators of other EPKs, by phosphorylating their activation-loop phosphorylation sites. Therefore, they function ‘upstream’ to their substrate EPKs. This organizes some EPKs in cells into signaling pathways that are composed of cascades of tiered kinases, in which some serve as upstream kinases for others in a hierarchical manner. Frequently, upstream kinases serve as dedicated kinases to their downstream EPKs and have no other substrates. Examples for this are the mitogen-activated protein kinase kinases that activate mitogen-activated protein kinase family members, phosphoinositide-dependent kinase 1 that serves as an upstream kinase for the AGC kinase family, and liver kinase B1 that serves as a master regulator of the AMP-activated protein kinase-related kinases.