Typical and atypical domain combinations in human protein kinases: functions, disease causing mutations and conservation in other primates

Ser/Thr and Tyr protein kinases orchestrate many signalling pathways and hence loss in this balance leads to many disease phenotypes. Due to their high abundance, diversity and importance, efforts have been made in the past to classify kinases and annotate their functions at both gross and fine levels. These kinases are conventionally classified into subfamilies based on the sequences of catalytic domains. Usually the domain architecture of a full-length kinase is consistent with the subfamily classification made based on the sequence of kinase domain. Important contributions of modular domains to the overall function of the kinase are well known. Recently occurrence of two kinds of outlier kinases-''Hybrid'' and ``Rogue'' has been reported. These show considerable deviations in their domain architectures from the typical domain architecture known for the classical kinase subfamilies. This article provides an overview of the different subfamilies of human kinases and the role of non-kinase domains in functions and diseases. Importantly this article provides analysis of hybrid and rogue kinases encoded in the human genome and highlights their conservation in closely related primate species. These kinases are examples of elegant rewiring to bring about subtle functional differences compared to canonical variants

Domain architectures of three rogue kinases.

<p>Domain architectures of corresponding classical kinase subfamily are also shown in each panel. Sequence identities of kinase domain of rogue kinase with that of the canonical kinase of classified sub-family A) 47%, B) 37%, C) 97%.</p

Market Access Advancements and Challenges in “Drug-Companion Diagnostic Test” Co-Development in Europe

The pharma ecosphere is witnessing a measured transformation from the one-size-fits-all or blockbuster model of drugs to more informed and tailored personalized treatments that facilitate higher safety and efficacy for a relevant sub-population. However, with several breakthroughs still in a nascent stage, market access becomes a crucial factor for commercial success, especially when it comes to co-creating value for pertinent stakeholders. This article highlights diverse issues from stakeholder perspectives in Europe, specifically the ones which require immediate resolution. Furthermore, the article also discusses case studies articulating potential solutions for the issues discussed

Graphs showing cluster analysis obtained upon hierarchical clustering of 1498 kinases.

<p>A) Entropy of various clusters, B) Proportion of hybrid/rogue kinases in clusters with high entropy.</p

Domain architectures of three multi-domain hybrid kinases (A, B, C).

<p>Canonical domain architectures of classified subfamily and source subfamily are shown. Sequence identity between kinase domains of hybrid and canonical members of classified subfamily, A) 83%, B) 84%, C) 49%.</p

Classification of <i>msh4/5</i> mutations that affect protein stability or interaction with DNA.

<p>Classification of <i>msh4/5</i> mutations that affect protein stability or interaction with DNA.</p

Molecular interactions of Msh5 residues involved in ATP hydrolysis and DNA binding.

<p>A) Side chain interactions of R685 with Q705 and D250 stabilize the β-sheet preceding R685. B) Aromatic-aromatic interactions between Y480, Y486, Y530 and Y534. Interactions are shown in dashed green lines.</p

Hybrid and Rogue Kinases Encoded in the Genomes of Model Eukaryotes

<div><p>The highly modular nature of protein kinases generates diverse functional roles mediated by evolutionary events such as domain recombination, insertion and deletion of domains. Usually domain architecture of a kinase is related to the subfamily to which the kinase catalytic domain belongs. However outlier kinases with unusual domain architectures serve in the expansion of the functional space of the protein kinase family. For example, Src kinases are made-up of SH2 and SH3 domains in addition to the kinase catalytic domain. A kinase which lacks these two domains but retains sequence characteristics within the kinase catalytic domain is an outlier that is likely to have modes of regulation different from classical src kinases. This study defines two types of outlier kinases: hybrids and rogues depending on the nature of domain recombination. Hybrid kinases are those where the catalytic kinase domain belongs to a kinase subfamily but the domain architecture is typical of another kinase subfamily. Rogue kinases are those with kinase catalytic domain characteristic of a kinase subfamily but the domain architecture is typical of neither that subfamily nor any other kinase subfamily. This report provides a consolidated set of such hybrid and rogue kinases gleaned from six eukaryotic genomes–<i>S.cerevisiae, D. melanogaster, C.elegans, M.musculus, T.rubripes</i> and <i>H.sapiens</i>–and discusses their functions. The presence of such kinases necessitates a revisiting of the classification scheme of the protein kinase family using full length sequences apart from classical classification using solely the sequences of kinase catalytic domains. The study of these kinases provides a good insight in engineering signalling pathways for a desired output. Lastly, identification of hybrids and rogues in pathogenic protozoa such as <i>P.falciparum</i> sheds light on possible strategies in host-pathogen interactions.</p></div

Msh4–Msh5 model highlighting the binding cavity for the Holliday junction.

<p>Panel A shows the cartoon representation and Panel B shows the surface representation of the model.</p

Residues predicted to occur at the interface of the Msh4–Msh5 heterodimer.

<p>Residues predicted to occur at the interface of the Msh4–Msh5 heterodimer.</p