Structural and functional diversity in the activity and regulation of DAPK‐related protein kinases

Abstract

Within the large group of calcium/calmodulin-dependent protein kinases (CAMKs) of the human kinome, there is a distinct branch of highly related kinases that includes three families: death-associated protein-related kinases, myosin light-chain-related kinases and triple functional domain proteinrelated kinases. In this review, we refer to these collectively as DMT kinases. There are several functional features that span the three families, such as a broad involvement in apoptotic processes, cytoskeletal association and cellular plasticity. Other CAMKs contain a highly conserved HRD motif, which is a prerequisite for kinase regulation through activation-loop phosphorylation, but in all 16 members of the DMT branch, this is replaced by an HF/LD motif. This DMT kinase signature motif substitutes phosphorylation-dependent active-site interactions with a local hydrophobic core that maintains an active kinase conformation. Only about half of the DMT kinases have an additional autoregulatory domain, C-terminal to the kinase domain that binds calcium/calmodulin in order to regulate kinase activity. Protein substrates have been identified for some of the DMT kinases, but little is known about the mechanism of recognition. Substrate conformation could be an equally important parameter in substrate recognition as specific preferences in sequence position. Taking the data together, this kinase branch encapsulates a treasure trove of features that renders it distinct from many other protein kinases and calls for future research activities in this field.

Structure of giant muscle proteins

“…These findings suggest that the molecular mechanism of kinase stretch activation is more complicated than first suspected, and may involve multiple other sites within titin (Ohlsson et al, 2012; Pfeffer et al, 2012). A more extensive review of the kinase domain can be found in Kontrogianni-Konstantopoulos et al (2009); Gautel (2011a); Temmerman et al (2013). …”

Serine/Threonine Kinase 17A Is a Novel Candidate for Therapeutic Targeting in Glioblastoma

“…STK17A (DRAK1) and STK17B (DRAK2) are more distantly related and less characterized members of the DAPK family [12-14]. DAPK1 is a multi-domain cytosolic actin filament-associated calcium/calmodulin-dependent, serine/threonine kinase that has a known regulatory role in cytoskeletal dynamics, apoptosis, autophagy, cell adhesion and motility [15-17].…”

DAPK-HSF1 interaction as a new positive feedback loop for TNF-induced apoptosis in colorectal cancer cells

“…Interestingly, these changes were noticeable as structural rearrangements at the DAPK-specific basic loop (residues 46-56), comprising the motif KRXXXXSRRG located at the upper lobe of the catalytic domain. The residues in this loop are highly exposed and face the catalytic site of DAPK (Temmerman et al, 2013). Besides this, there are significant structural rearrangements in the activation segment (residues 163-186), surface loops (residues 22-25 and 213-221) and in the N-terminal helix A (residues 8-12) of DAPK.…”