Community analysis of large-scale molecular dynamics simulations
elucidated dynamics-driven allostery in Tyrosine kinase 2
Abstract
TYK2 is a non-receptor tyrosine kinase, member of the Janus kinases
(JAK), with a central role in several diseases, including cancer. The
JAKs’ catalytic domains (KD) are highly conserved, yet the isolated
TYK2-KD exhibits unique specificities. In a previous work, using
molecular dynamics (MD) simulations of a catalytically-impaired TYK2-KD
variant (P1104A) we found that this amino-acid change of its
JAK-characteristic insert (αFG), acts at the dynamics level. Given that
structural dynamics is key to allosteric activation of protein kinases,
in this study we applied a long-scale MD simulation and investigated an
active TYK2-KD form in the presence of adenosine 5’-triphosphate and one
magnesium ion that represents a dynamic and crucial step of the
catalytic cycle, in other protein kinases. Community analysis of the MD
trajectory shed light, for the first time, on the dynamic profile and
dynamics-driven allosteric communications within the TYK2-KD during
activation and revealed that αFG and amino-acids P1104, P1105 and I1112
in particular, hold a pivotal role and act synergistically with a
dynamically coupled communication network of amino-acids serving
intra-KD signaling for allosteric regulation of TYK2 activity.
Corroborating our findings, most of the identified amino-acids are
associated with cancer-related missense/splice-site mutations of the
Tyk2 gene. We propose that the conformational dynamics at this
step of the catalytic cycle, coordinated by αFG, underlies TYK2-unique
substrate recognition and accounts for its distinct specificity. In
total, this work adds to knowledge towards an in-depth understanding of
TYK2 activation and may be valuable towards a rational design of
allosteric TYK2-specific inhibitors.