Crystal Structure of Ripk4 Reveals Dimerization-Dependent Kinase Activity

Huang, Christine; Oberbeck, Nina; Hsiao, Yi-Chun; Liu, Peter; Johnson, Adam R.; Dixit, Vishva M.; Hymowitz, S.G.

doi:10.1016/j.str.2018.04.002

Cited by 20 publications

(18 citation statements)

References 41 publications

(43 reference statements)

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“…However, the interaction between RIPK4 and KRT14 was particularly mediated by RIPK4's N-terminal kinase domain ( Figure 1B). Previously, RIPK4's kinase activity was shown to be dispensable for RIPK4 interaction with IRF6 (Huang et al, 2018). Similar to this report, our result showed that RIPK4 kinase activity is not necessary for RIPK4/KRT14 interaction ( Figure 1C).…”

Section: Discussionsupporting

confidence: 90%

Keratin 14 is a novel interaction partner of keratinocyte differentiation regulator: receptor-interacting protein kinase 4

Sümer

Dinçer

2019

Turk J Biol

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The epidermis is a stratified epithelium that protects the organism against environmental insults. The maintenance of the epidermis is provided by sustained proliferation and differentiation of the keratinocyte stem cells localized to the basal layer of the epidermis (Fuchs and Nowak, 2008; Blanpain and Fuchs, 2009). As keratinocyte stem cells commit to differentiate, they cease to proliferate and start to move upward to form suprabasal layers, including spinous, granular, and stratum corneum with different biochemical contents and morphologies (Fuchs and Nowak, 2008). In this differentiation process, transcription factor p63, which is the well-known master regulator of keratinocyte differentiation, regulates the expression of a plethora of proteins involved in keratinocyte differentiation and maintenance, including receptor-interacting protein kinase 4 (RIPK4), interferon regulatory factor 6 (IRF6), inhibitory kappa B kinase α (IKKα), and keratin 14 (KRT14)

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Section: Discussionsupporting

confidence: 90%

Keratin 14 is a novel interaction partner of keratinocyte differentiation regulator: receptor-interacting protein kinase 4

Sümer

Dinçer

2019

Turk J Biol

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“…Interestingly, Ser25 is also present in RIPK2 and in RIPK4 (Fig. 6a) and crystal structures of active RIPK2 53,54 and RIPK4 55 indicate that Ser25 helps to seal the nucleotide binding site near the ribose and α-phosphate of the bound nucleotide (Fig. 6c).…”

Section: Resultsmentioning

confidence: 99%

Serine 25 phosphorylation inhibits RIPK1 kinase-dependent cell death in models of infection and inflammation

et al. 2019

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RIPK1 regulates cell death and inflammation through kinase-dependent and -independent mechanisms. As a scaffold, RIPK1 inhibits caspase-8-dependent apoptosis and RIPK3/MLKL-dependent necroptosis. As a kinase, RIPK1 paradoxically induces these cell death modalities. The molecular switch between RIPK1 pro-survival and pro-death functions remains poorly understood. We identify phosphorylation of RIPK1 on Ser25 by IKKs as a key mechanism directly inhibiting RIPK1 kinase activity and preventing TNF-mediated RIPK1-dependent cell death. Mimicking Ser25 phosphorylation (S > D mutation) protects cells and mice from the cytotoxic effect of TNF in conditions of IKK inhibition. In line with their roles in IKK activation, TNF-induced Ser25 phosphorylation of RIPK1 is defective in TAK1- or SHARPIN-deficient cells and restoring phosphorylation protects these cells from TNF-induced death. Importantly, mimicking Ser25 phosphorylation compromises the in vivo cell death-dependent immune control of Yersinia infection, a physiological model of TAK1/IKK inhibition, and rescues the cell death-induced multi-organ inflammatory phenotype of the SHARPIN-deficient mice.

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“…The catalytic domain crystal structure (5WNI) of mouse RIPK4 from Protein Data Bank (PDB) was used to analyze the effect of Asp161His substitution (Huang et al, 2018). Since, the conserved Asp143 residue had been replaced with Asn in the 5WNI model, we converted this substitution to the wild type amino acid (Asp).…”

Section: Methodsmentioning

confidence: 99%

A novel homozygous RIPK4 variant in a family with severe Bartsocas‐Papas syndrome

Dinçer

Gümüş

Toraman

et al. 2021

American J of Med Genetics Pt A

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Bartsocas‐Papas syndrome (BPS) is a rare autosomal recessive disorder characterized by popliteal pterygia, syndactyly, ankyloblepharon, filiform bands between the jaws, cleft lip and palate, and genital malformations. Most of the BPS cases reported to date are fatal either in the prenatal or neonatal period. Causative genetic defects of BPS were mapped on the RIPK4 gene encoding receptor‐interacting serine/threonine kinase 4, which is critical for epidermal differentiation and development. RIPK4 variants are associated with a wide range of clinical features ranging from milder ectodermal dysplasia to severe BPS. Here, we evaluated a consanguineous Turkish family, who had two pregnancies with severe multiple malformations compatible with BPS phenotype. In order to identify the underlying genetic defect, direct sequencing of the coding region and exon‐intron boundaries of RIPK4 was carried out. A homozygous transversion (c.481G>C) that leads to the substitution of a conserved aspartic acid to histidine (p.Asp161His) in the kinase domain of the protein was detected. Pathogenicity predictions, molecular modeling, and cell‐based functional assays showed that Asp161 residue is required for the kinase activity of the protein, which indicates that the identified variant is responsible for the severe BPS phenotype in the family.

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Crystal Structure of Ripk4 Reveals Dimerization-Dependent Kinase Activity

Cited by 20 publications

References 41 publications

Keratin 14 is a novel interaction partner of keratinocyte differentiation regulator: receptor-interacting protein kinase 4

Keratin 14 is a novel interaction partner of keratinocyte differentiation regulator: receptor-interacting protein kinase 4

Serine 25 phosphorylation inhibits RIPK1 kinase-dependent cell death in models of infection and inflammation

A novel homozygous RIPK4 variant in a family with severe Bartsocas‐Papas syndrome

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