HRD Motif as the Central Hub of the Signaling Network for Activation Loop Autophosphorylation in Abl Kinase.
A number of structural factors modulate the activity of Abelson (Abl) tyrosine kinase, whose deregulation is often related to oncogenic processes. First, only the open conformation of the Abl kinase domain's activation loop (A-loop) favors ATP binding to the catalytic cleft. In this regard, the trans-autophosphorylation of the Y412 residue, which is located along the A-loop, favors the stability of the open conformation, in turn enhancing Abl activity. Another key factor for full Abl activity is the formation of active conformations of the catalytic DFG motif in the Abl kinase domain. Furthermore, binding of the SH2 domain to the N-lobe of the Abl kinase was recently demonstrated to have a long-range allosteric effect on the stabilization of the A-loop open state. Intriguingly, these distinct structural factors imply a complex signal transmission network for controlling the A-loop's flexibility and conformational preference for optimal Abl function. However, the exact dynamical features of this signal transmission network structure remain unclear. Here, we report on microsecond-long molecular dynamics coupled with enhanced sampling simulations of multiple Abl model systems, in the presence or absence of the SH2 domain and with the DFG motif flipped in two ways (in or out conformation). Through comparative analysis, our simulations augment the interpretation of the existing Abl experimental data, revealing a dynamical network of interactions that interconnect SH2 domain binding with A-loop plasticity and Y412 autophosphorylation in Abl. This signaling network engages the DFG motif and, importantly, other conserved structural elements of the kinase domain, namely, the EPK-ELK H-bond network and the HRD motif. Our results show that the signal propagation for modulating the A-loop spatial localization is highly dependent on the HRD motif conformation, which thus acts as the central hub of this (allosteric) signaling network controlling Abl activation and function.
Giuseppina
G
La Sala
Laura
L
Riccardi
Roberto
R
Gaspari
Department of Pharmacy & Biotechnology, Alma Mater Studiorum, University of Bologna , Via Belmeloro 6, 40126 Bologna, Italy.
Andrea
A
Cavalli
Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, École polytechnique fédérale de Lausanne (EPFL) , 1015 Lausanne, Switzerland.|ISREC Foundation Chair in Translational Oncology , 1015 Lausanne, Switzerland.
Oliver
O
Hantschel
IAS-S/INM-9 Computational Biomedicine Forschungszentrum , Jülich Wilhelm-Johnen-Staße, 52428 Jülich, Germany.
Marco
M
De Vivo
D020816:Amino Acid Motifs; D006860:Hydrogen Bonding; D056004:Molecular Dynamics Simulation; D010766:Phosphorylation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D016315:Proto-Oncogene Proteins c-abl / Q000737:chemistry* / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D018909:src Homology Domains
D016315:Proto-Oncogene Proteins c-abl