Nucleotide Binding, Evolutionary Insights, and Interaction Partners of the Pseudokinase Unc-51-like Kinase 4

Abstract

Highlights d Structure of the ULK4 ATP complex reveals a unique ATP binding mode d Disease-associated mutations modulate ATP binding and ULK4 stability d Loss of canonical motifs co-occurred in evolution with a specific activation loop d BioID suggests a role of ULK4 regulating centrosomal and cytoskeletal functions

There’s more to death than life: Noncatalytic functions in kinase and pseudokinase signaling

“…Where TRIB1 appears to have eschewed the ability to bind ATP, this is not necessarily universal among scaffolding pseudokinases. There are reports that TRIB2 and TRIB3 retain some weak nucleotide binding and activity ( 80 ), and the ULK4 pseudokinase, which putatively functions as a protein scaffold, can bind ATP ( 9 , 81 , 82 ). The ULK4-ATP-binding mechanism is quite unconventional, whereby an alternative lysine residue compensates for the lack of an intact VAIK motif ( 81 ).…”

“…B , close-up view of the PKA active site, with key catalytic features described in the text indicated. C , examples of the four classes of pseudokinase active site exemplified by TRIB1 (PDB 6dc0; ( 75 )), ULK4 (PDB 6tsz; ( 81 )), SgK269 (PDB 6bhc; ( 67 )), and HER3 (PDB 3kex; ( 109 )). For each, the Gly-loop, VAIK-motif, αC-helix, DFG-motif, and HRD catalytic loop are depicted, and pseudokinases that bind nucleotide (either without or with Mg 2+ ; Classes 2/4) also have the nucleotide-binding site shown as a cyan surface.…”

Ulk4, a Newly Discovered Susceptibility Gene for Schizophrenia, Regulates Corticogenesis in Mice

“…In our mice, increased apoptosis could be detected as early as E17.5 ( Figure 5A ), a key developmental time window when the ventricles were not ciliated, and culminated at P7 ( Figure 5A ), when the multi-ciliated ependymal cells are supposed to appear ( Banizs et al, 2005 ). Recently, the structure of Ulk4 was resolved and interacting partners were reported, including tubulin binding and centrosomal proteins ( Khamrui et al, 2020 ; Preuss et al, 2020 ), such as HAUS2 and HAUS8 ( Uehara et al, 2009 ), CCP110 (centriolar coiled-coil protein 110), CEP97 (centrosomal protein 97), CSPP1 (centrosome and spindle pole-associated protein 1), and OFD1 (OFD1 centriole and centriolar satellite protein), and motor proteins of the kinesin family (KIF1B, KIF3B, and KIFAP3). These proteins were widely involved in the cell cycle, cell polarity, and cytoskeleton arrangement, highlighting the role of Ulk4 in cell division and migration of neuronal progenitors.…”

Conformational plasticity of the ULK3 kinase domain

“…Several sequence motifs that are typically found in kinases and that are indispensable for catalytic activity are not conserved in ULK4. Two ULK4 structure models have recently been published, one showing ULK4 in complex with its physiological cofactor ATP 22 , and one in complex with a low-affinity inhibitor 23 . Again, there is no indication for domain plasticity -ATP binds tightly to the pseudoactive site and condenses ULK4 as also shown in MD simulations.…”

“…Again, there is no indication for domain plasticity -ATP binds tightly to the pseudoactive site and condenses ULK4 as also shown in MD simulations. 22 In contrast, structural information on the ULK3 and STK36 kinase domains is still lacking. The understanding of their complex functional roles both in physiology and in pathophysiology will be aided by high-resolution structure models that provide insight into their regulation as well as by selective chemical probes that can be used in cellular model systems or in vivo to study ULK function.…”