PIM-1L kinase binds to and inactivates SRPK1: A Biochemical and
Molecular Dynamics Study
Abstract
SR/RS dipeptide repeats vary in both length and position and are
phosphorylated by SR protein kinases (SRPKs). PIM-1L, the long isoform
of PIM-1 kinase, the splicing of which has been implicated in acute
myeloid leukemia, contains a domain which consists largely of repeating
SR/RS and SH/HS dipeptides (SR/SH-rich). In order to extend our
knowledge on the specificity and cellular functions of SRPK1, here we
investigate whether PIM-1L could act as substrate of SRPK1 by a
combination of biochemical and computational approaches. Our biochemical
data showed that the SR/SH-rich domain of PIM-1L was able to associate
with SRPK1, yet it could not act as a substrate but, instead,
inactivated the kinase. In line with our biochemical data, molecular
modeling followed by a microsecond-scale all-atom molecular dynamics
(MD) simulation suggests that the SR/SH-rich domain acts as a
pseudo-docking peptide that binds to the same acidic docking-groove used
in other SRPK1 interactions and induces inactive SRPK1 conformations.
Comparative community network analysis of the MD trajectories, unraveled
the dynamic architecture of apo SRPK1 and notable alterations of
allosteric communications upon PIM-1L peptide binding. This analysis
also allowed us to identify key SRPK1 residues, including unique ones,
with a pivotal role in mediating allosteric signal propagation within
the kinase core. Interestingly, most of the identified amino acids
correspond to cancer-associated amino acid changes, validating our
results. In total, this work provides insights not only on the details
of SRPK1 inhibition by the PIM-1L SR/SH-domain, but also contributes to
an in-depth understanding of SRPK1 regulation.