New insights into the structural dynamics of the kinase JNK3

Abstract

In this work, we study the dynamics and the energetics of the all-atom structure of a neuronal-specific serine/threonine kinase c-Jun N-terminal kinase 3 (JNK3) in three states: unphosphorylated, phosphorylated, and ATP-bound phosphorylated. A series of 2 µs atomistic simulations followed by a conformational landscape mapping and a principal component analysis supports the mechanistic understanding of the JNK3 inactivation/activation process and also indicates key structural intermediates. Our analysis reveals that the unphosphorylated JNK3 undergoes the ‘open-to-closed’ movement via a two-step mechanism. Furthermore, the phosphorylation and ATP-binding allow the JNK3 kinase to attain a fully active conformation. JNK3 is a widely studied target for small-drugs used to treat a variety of neurological disorders. We believe that the mechanistic understanding of the large-conformational changes upon the activation of JNK3 will aid the development of novel targeted therapeutics.

JNK3 as Therapeutic Target and Biomarker in Neurodegenerative and Neurodevelopmental Brain Diseases

“…The location of this non-conserved region suggests an extended substrate-binding site in JNK3 that may be important for substrate-binding specificity. Unfortunately, no crystal structures describing the full structure of JNK3 are currently available; the first N -terminal and the last C -terminal residues are missing in the available crystal coordinates [ 46 ]. However, JNKs show a different specificity towards their scaffold proteins.…”

Involvement of JNK1 in Neuronal Polarization During Brain Development

“…Several motifs are necessary to regulate the enzymatic reaction: the activation domain (A-loop) contains the TPY sequence, and a conserved G-loop (Glycine-Rich) motif is necessary to close the ATP-binding domain. The HRD motif is involved in the reaction mechanics; meanwhile, the DRG sequence is critical for conformational changing in the reaction [20,21]. JNKs also contain D-recruiting site (DRS).…”

“…JNKs also contain D-recruiting site (DRS). This sequence is necessary for interactions with their cognate sequence D-motif, found in substrates or scaffold-protein-like JIP [21]. In general, the catalytic site is conserved (See protein alignment for the main JNK isoform, Supplementary Materials Table S1)…”

The Regulation of JNK Signaling Pathways in Cell Death through the Interplay with Mitochondrial SAB and Upstream Post-Translational Effects

“…JNK and p38 are activated by MKK4/7 via dual phosphorylation of a Thr-Pro-Tyr (TPY) motif of the activation loop (A-loop), which connects N-terminal and C-terminal lobes. The ATP binding site lies between the lobes [ 16 ]. One critical feature of JNK signaling is the use of its single common docking site (CD) to interact with JNK-binding domain (D-motif) of upstream MKKs, MAP kinase phosphatases, substrates, inhibitors, and scaffold proteins.…”