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Review
. 2021 Jan:109:96-105.
doi: 10.1016/j.semcdb.2020.06.014. Epub 2020 Jul 27.

RIPK protein kinase family: Atypical lives of typical kinases

Gregory D Cuny  1 , Alexei Degterev  2
Affiliations
Review

RIPK protein kinase family: Atypical lives of typical kinases

Gregory D Cuny et al. Semin Cell Dev Biol. 2021 Jan.

Abstract

Receptor Interacting Protein Kinases (RIPKs) are a family of Ser/Thr/Tyr kinases whose functions, regulation and pathophysiologic roles have remained an enigma for a long time. In recent years, these proteins garnered significant interest due to their roles in regulating a variety of host defense functions including control of inflammatory gene expression, different forms of cell death, and cutaneous and intestinal barrier functions. In addition, there is accumulating evidence that while these kinases seemingly follow typical kinase blueprints, their functioning in cells can take forms that are atypical for protein kinases. Lastly, while these kinases generally belong to distinct areas of innate immune regulation, there are emerging overarching themes that may unify the functions of this kinase family. Our review seeks to discuss the biology of RIPKs, and how typical and atypical features of this family informs the activity of a rapidly growing repertoire of RIPK inhibitors.

Keywords: RIPK1; RIPK2; RIPK3; RIPK4; RIPK5; apoptosis; inflammation; kinase; necroptosis.

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Figures

Figure 1.
Figure 1.
RIPKs belong to the Tyrosine Kinase-Like (TKL) subfamily of human kinases. RIPK family members are shown in green (ANKRD3 is RIPK4, SgK288 or SgK496 is RIPK5, see text for further details). Related TKL kinases are shown in red. Illustration reproduced courtesy of Cell Signaling Technology, Inc. (www.cellsignal.com).
Figure 2.
Figure 2.
A) Domain architecture of RIPKs. B) Alignment of the critical catalytic elements of RIPKs. * indicate critical residues in each motif, * depict RIPK1 autophosphorylation sites Ser161 and Ser166. C) Phylogenic tree of RIPK kinase domains. Alignments in B and C were generated using UGENE software package and T-Coffee alignment algorithm. D) Degree of similarity between RIPKs was calculated in UGENE using the built-in similarity matrix. Alignment was also performed using ClustalW with similar results.
Figure 3.
Figure 3.
Structural features of RIPKs. A) The size and flexibility of the side chains of Met92 gatekeeper and Leu157 of the DLG define access into the allosteric back-pocket of RIPK1. Based on Glu-in/DLG-out structure 4NEU. Figures were generated using the Schrödinger Maestro software package. B) Arg142 of the HRD motif of RIPK3 is in sufficient proximity to Ser165 in the activation loop. We propose that phosphorylation of Ser165 will result in mutual rotation (arrow) of the two side chains to enable interaction. Based on the active Glu-in/DFG-in structure 4M66.
Figure 4.
Figure 4.
A) Representative examples of RIPK1 inhibitors. B) Representative examples of RIPK3 inhibitors.
Figure 5.
Figure 5.
Representative examples of RIPK2 inhibitors.
Figure 6.
Figure 6.
A,B) Alignment of the DFG-in/Glu-in active conformations of RIPKs. A – entire kinase domains, B – ATP-binding pockets. C) Alignment of inactive DFG-out/Glu-in conformations of RIPKs.
Figure 7.
Figure 7.
A) Alignment of the Nec-1s bound to RIPK1 in the DLG-out/Glu-out conformation (4ITH, blue) vs. the model of the active RIPK1 conformation, generated using homology modeling (red). Nec-1s binds exclusively in RIPK1 back pocket between activation segment and αC helix. This conformation is associated with the outward movement of the αC helix (arrow), breaking an ionic interaction of Glu63 with catalytic Lys45 and rotation of the DLG motif into the inactive conformation where the side-chain of Asp is not aligned with the ATP pocket. B) Binding of Nec-1s is mediated by three hydrogen bonds, including to the side chain of Ser161, an autophosphorylation site at the N-terminus of the activation loop. It is also stabilized by hydrophobic interactions, especially with the side-chains of Met67 in the αC helix and Phe162 in the activation loop.
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