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Article ; Online: Marveling at the Incredible ULK4.

Eyers, Patrick A

Structure (London, England : 1993)

2020 Volume 28, Issue 11, Page(s) 1181–1183

Abstract: Unc-51-like kinase 4 (ULK4) is a pseudokinase conserved in most eukaryotes, yet ULK4 signaling mechanisms remain enigmatic. In this issue of Structure, Preuss and colleagues report a structure of the ATP-bound ULK4 pseudokinase domain, supported by ... ...

Abstract	Unc-51-like kinase 4 (ULK4) is a pseudokinase conserved in most eukaryotes, yet ULK4 signaling mechanisms remain enigmatic. In this issue of Structure, Preuss and colleagues report a structure of the ATP-bound ULK4 pseudokinase domain, supported by proteomic analysis of the ULK4 interactome and in-depth evolutionary analysis of the intriguingULK4 pseudokinase domain.
MeSH term(s)	Nucleotides ; Protein Serine-Threonine Kinases/genetics ; Protein Serine-Threonine Kinases/metabolism ; Proteomics ; Signal Transduction
Chemical Substances	Nucleotides ; Protein Serine-Threonine Kinases (EC 2.7.11.1)
Language	English
Publishing date	2020-10-27
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	1213087-4
ISSN	1878-4186 ; 0969-2126
ISSN (online)	1878-4186
ISSN	0969-2126
DOI	10.1016/j.str.2020.10.005
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Article ; Online: A new consensus for evaluating CDKL5/STK9-dependent signalling mechanisms.

Eyers, Patrick A

The EMBO journal

2018 Volume 37, Issue 24

MeSH term(s)	Animals ; Epileptic Syndromes/genetics ; Epileptic Syndromes/metabolism ; Epileptic Syndromes/pathology ; Humans ; Microtubules/genetics ; Microtubules/metabolism ; Phosphorylation/genetics ; Protein-Serine-Threonine Kinases/genetics ; Protein-Serine-Threonine Kinases/metabolism ; Signal Transduction ; Spasms, Infantile/genetics ; Spasms, Infantile/metabolism ; Spasms, Infantile/pathology
Chemical Substances	Protein-Serine-Threonine Kinases (EC 2.7.11.1) ; CDKL5 protein, human (EC 2.7.11.22)
Language	English
Publishing date	2018-10-30
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	586044-1
ISSN	1460-2075 ; 0261-4189
ISSN (online)	1460-2075
ISSN	0261-4189
DOI	10.15252/embj.2018100848
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Article ; Online: Back to the future: new target-validated Rab antibodies for evaluating LRRK2 signalling in cell biology and Parkinson's disease.

Eyers, Patrick A

The Biochemical journal

2018 Volume 475, Issue 1, Page(s) 185–189

Abstract: The addition of phosphate groups to substrates allows protein kinases to regulate a myriad of biological processes, and contextual analysis of protein-bound phosphate is important for understanding how kinases contribute to physiology and disease. ... ...

Abstract	The addition of phosphate groups to substrates allows protein kinases to regulate a myriad of biological processes, and contextual analysis of protein-bound phosphate is important for understanding how kinases contribute to physiology and disease. Leucine-rich repeat kinase 2 (LRRK2) is a Ser/Thr kinase linked to familial and sporadic cases of Parkinson's disease (PD). Recent work established that multiple Rab GTPases are physiological substrates of LRRK2, with Rab10 in particular emerging as a human substrate whose site-specific phosphorylation mirrors hyperactive LRRK2 lesions associated with PD. However, current assays to quantify Rab10 phosphorylation are expensive, time-consuming and technically challenging. In back-to-back studies reported in the
MeSH term(s)	Antibodies, Phospho-Specific ; Biological Phenomena ; Humans ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 ; Parkinson Disease ; Signal Transduction
Chemical Substances	Antibodies, Phospho-Specific ; LRRK2 protein, human (EC 2.7.11.1) ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 (EC 2.7.11.1)
Language	English
Publishing date	2018-01-05
Publishing country	England
Document type	Journal Article ; Comment
ZDB-ID	2969-5
ISSN	1470-8728 ; 0006-2936 ; 0306-3275 ; 0264-6021
ISSN (online)	1470-8728
ISSN	0006-2936 ; 0306-3275 ; 0264-6021
DOI	10.1042/BCJ20170870
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Article ; Online: Custom Workflow for the Confident Identification of Sulfotyrosine-Containing Peptides and Their Discrimination from Phosphopeptides.

Daly, Leonard A / Byrne, Dominic P / Perkins, Simon / Brownridge, Philip J / McDonnell, Euan / Jones, Andrew R / Eyers, Patrick A / Eyers, Claire E

Journal of proteome research

2023 Volume 22, Issue 12, Page(s) 3754–3772

Abstract: Protein tyrosine sulfation (sY) is a post-translational modification (PTM) catalyzed by Golgi-resident tyrosyl protein sulfo transferases (TPSTs). Information on sY in humans is currently limited to ∼50 proteins, with only a handful having verified sites ...

Abstract	Protein tyrosine sulfation (sY) is a post-translational modification (PTM) catalyzed by Golgi-resident tyrosyl protein sulfo transferases (TPSTs). Information on sY in humans is currently limited to ∼50 proteins, with only a handful having verified sites of sulfation. As such, the contribution of sulfation to the regulation of biological processes remains poorly defined. Mass spectrometry (MS)-based proteomics is the method of choice for PTM analysis but has yet to be applied for systematic investigation of the "sulfome", primarily due to issues associated with discrimination of sY-containing from phosphotyrosine (pY)-containing peptides. In this study, we developed an MS-based workflow for sY-peptide characterization, incorporating optimized Zr
MeSH term(s)	Humans ; Phosphopeptides/analysis ; HEK293 Cells ; Workflow ; Tyrosine/metabolism ; Proteins ; Phosphotyrosine
Chemical Substances	Phosphopeptides ; tyrosine O-sulfate (29166358BF) ; Tyrosine (42HK56048U) ; Proteins ; Phosphotyrosine (21820-51-9)
Language	English
Publishing date	2023-11-08
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2078618-9
ISSN	1535-3907 ; 1535-3893
ISSN (online)	1535-3907
ISSN	1535-3893
DOI	10.1021/acs.jproteome.3c00425
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Article: Redox Regulation of Brain Selective Kinases BRSK1/2: Implications for Dynamic Control of the Eukaryotic AMPK family through Cys-based mechanisms.

Bendzunas, George N / Byrne, Dominic P / Shrestha, Safal / Daly, Leonard A / Oswald, Sally O / Katiyar, Samiksha / Venkat, Aarya / Yeung, Wayland / Eyers, Claire E / Eyers, Patrick A / Kannan, Natarajan

bioRxiv : the preprint server for biology

2024

Abstract: In eukaryotes, protein kinase signaling is regulated by a diverse array of post-translational modifications (PTMs), including phosphorylation of Ser/Thr residues and oxidation of cysteine (Cys) residues. While regulation by activation segment ... ...

Abstract	In eukaryotes, protein kinase signaling is regulated by a diverse array of post-translational modifications (PTMs), including phosphorylation of Ser/Thr residues and oxidation of cysteine (Cys) residues. While regulation by activation segment phosphorylation of Ser/Thr residues is well understood, relatively little is known about how oxidation of cysteine residues modulate catalysis. In this study, we investigate redox regulation of the AMPK-related Brain-selective kinases (BRSK) 1 and 2, and detail how broad catalytic activity is directly regulated through reversible oxidation and reduction of evolutionarily conserved Cys residues within the catalytic domain. We show that redox-dependent control of BRSKs is a dynamic and multilayered process involving oxidative modifications of several Cys residues, including the formation of intramolecular disulfide bonds involving a pair of Cys residues near the catalytic HRD motif and a highly conserved T-Loop Cys with a BRSK-specific Cys within an unusual CPE motif at the end of the activation segment. Consistently, mutation of the CPE-Cys increases catalytic activity
Language	English
Publishing date	2024-04-10
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.10.05.561145
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Article ; Online: 'Up with the LRRK': a phosphorylated Rab10 assay for evaluation of LRRK2 activity and inhibitor engagement.

Eyers, Patrick A

The Biochemical journal

2016 Volume 473, Issue 18, Page(s) 2757–2762

Abstract: Protein kinases catalyse the addition of phosphate groups to Ser/Thr and Tyr residues in cognate substrates and are mutated or hyperactive in a variety of diseases, making them important targets for rationally designed drugs. A good example is the ... ...

Abstract	Protein kinases catalyse the addition of phosphate groups to Ser/Thr and Tyr residues in cognate substrates and are mutated or hyperactive in a variety of diseases, making them important targets for rationally designed drugs. A good example is the Parkinson's disease-associated kinase, leucine-rich repeat kinase 2 (LRRK2), which is mutated (and probably hyperactive) in a small, but significant, subset of patients. An exciting new approach for personalised therapy is the development of central nervous system (CNS)-active small-molecule kinase inhibitors, which could be employed to 'normalise' LRRK2 signalling in affected cell types. However, the development of such drugs requires validated assays for the analysis of target engagement and the assembly of a set of tools for interrogating LRRK2, and its substrates, both in vitro and in vivo A new study published in the Biochemical Journal by Ito et al. establishes that a 'Phos-tag'™-binding assay can be exploited to measure phosphorylation of a recently identified LRRK2 substrate (Ras-related protein in brain 10 (Rab10)), and to compare and contrast relative catalytic output from disease-associated LRRK2 mutants. Powerful in vivo chemical genetic approaches are also disclosed, in which the catalytic activity of LRRK2 is unequivocally linked to the extent of Rab10 phosphorylation and the effects of chemically distinct LRRK2 inhibitors are matched with on-target inhibition mechanisms mediated through LRRK2 and its substrate Rab10. These important findings should simplify the generic analysis of Rab10 phosphorylation in model biological systems and are likely to be applicable to other substrates of LRRK2 (or indeed other kinases) for which phospho-specific antibodies are either absent or unsatisfactory.
MeSH term(s)	Humans ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/antagonists & inhibitors ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/metabolism ; Phosphorylation ; Protein Kinase Inhibitors/pharmacology ; Protein Transport ; rab GTP-Binding Proteins/metabolism
Chemical Substances	Protein Kinase Inhibitors ; LRRK2 protein, human (EC 2.7.11.1) ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 (EC 2.7.11.1) ; Rab10 protein, human (EC 3.6.1.-) ; rab GTP-Binding Proteins (EC 3.6.5.2)
Language	English
Publishing date	2016-09-06
Publishing country	England
Document type	Journal Article ; Comment
ZDB-ID	2969-5
ISSN	1470-8728 ; 0006-2936 ; 0306-3275 ; 0264-6021
ISSN (online)	1470-8728
ISSN	0006-2936 ; 0306-3275 ; 0264-6021
DOI	10.1042/BCJ20160671C
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Article ; Online: Analysis of human Tribbles 2 (TRIB2) pseudokinase.

Harris, John A / Fairweather, Emma / Byrne, Dominic P / Eyers, Patrick A

Methods in enzymology

2022 Volume 667, Page(s) 79–99

Abstract: Human Tribbles 2 (TRIB2) is a cancer-associated pseudokinase with a broad human protein interactome, including the well-studied AKT, C/EBPα and MAPK modules. Several lines of evidence indicate that human TRIB2 promotes cell survival and drug-resistance ... ...

Abstract	Human Tribbles 2 (TRIB2) is a cancer-associated pseudokinase with a broad human protein interactome, including the well-studied AKT, C/EBPα and MAPK modules. Several lines of evidence indicate that human TRIB2 promotes cell survival and drug-resistance in solid tumors and blood cancers and is therefore of interest as a potential therapeutic target, although its physiological functions remain relatively poorly understood. The unique TRIB2 pseudokinase domain lacks the canonical 'DFG' motif, and subsequently possesses very low affinity for ATP in both the presence and absence of metal ions. However, TRIB2 also contains a unique cysteine-rich αC-helix, which interacts with a conserved peptide motif in its own carboxyl-terminal tail. This regulatory flanking region drives regulated interactions with distinct E3 ubiquitin ligases that serve to control the stability and turnover of TRIB2 client proteins. TRIB2 is also a low-affinity target of several known small-molecule protein kinase inhibitors, which were originally identified using purified recombinant TRIB2 proteins and a thermal shift assay. In this chapter, we discuss laboratory-based procedures for purification, stabilization and analysis of human TRIB2, including screening procedures that can be used for the identification of both reversible and covalent small molecule ligands.
MeSH term(s)	Calcium-Calmodulin-Dependent Protein Kinases/genetics ; Calcium-Calmodulin-Dependent Protein Kinases/metabolism ; Humans ; Intracellular Signaling Peptides and Proteins/genetics ; Neoplasms/pathology ; Ubiquitin-Protein Ligases/metabolism
Chemical Substances	Intracellular Signaling Peptides and Proteins ; Ubiquitin-Protein Ligases (EC 2.3.2.27) ; Calcium-Calmodulin-Dependent Protein Kinases (EC 2.7.11.17) ; TRIB2 protein, human (EC 2.7.11.17)
Language	English
Publishing date	2022-04-13
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	1557-7988
ISSN (online)	1557-7988
DOI	10.1016/bs.mie.2022.03.025
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Article ; Online: TRIBBLES: A Twist in the Pseudokinase Tail.

Eyers, Patrick A

Structure (London, England : 1993)

2015 Volume 23, Issue 11, Page(s) 1974–1976

Abstract: TRIB1, a homolog of Drosophila Tribbles, regulates the stability of transcription factors through physical interaction with the ubiquitin E3 ligase COP1. In this issue of Structure, Murphy et al. (2015) report the first X-ray analysis of the TRIB1 ... ...

Abstract	TRIB1, a homolog of Drosophila Tribbles, regulates the stability of transcription factors through physical interaction with the ubiquitin E3 ligase COP1. In this issue of Structure, Murphy et al. (2015) report the first X-ray analysis of the TRIB1 pseudokinase domain and its C-terminal COP1-binding extension.
MeSH term(s)	Animals ; Intracellular Signaling Peptides and Proteins ; Models, Molecular ; Protein Binding ; Transcription Factors/chemistry ; Ubiquitin-Protein Ligases/metabolism
Chemical Substances	Intracellular Signaling Peptides and Proteins ; Transcription Factors ; Ubiquitin-Protein Ligases (EC 2.3.2.27)
Language	English
Publishing date	2015-11-03
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	1213087-4
ISSN	1878-4186 ; 0969-2126
ISSN (online)	1878-4186
ISSN	0969-2126
DOI	10.1016/j.str.2015.10.003
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Article ; Online: Discovery of a Cushing's syndrome protein kinase A mutant that biases signaling through type I AKAPs.

Omar, Mitchell H / Byrne, Dominic P / Shrestha, Safal / Lakey, Tyler M / Lee, Kyung-Soon / Lauer, Sophia M / Collins, Kerrie B / Daly, Leonard A / Eyers, Claire E / Baird, Geoffrey S / Ong, Shao-En / Kannan, Natarajan / Eyers, Patrick A / Scott, John D

Science advances

2024 Volume 10, Issue 8, Page(s) eadl1258

Abstract: Adrenal Cushing's syndrome is a disease of cortisol hypersecretion often caused by mutations in protein kinase A catalytic subunit (PKAc). Using a personalized medicine screening platform, we discovered a Cushing's driver mutation, PKAc-W196G, in ~20% of ...

Abstract	Adrenal Cushing's syndrome is a disease of cortisol hypersecretion often caused by mutations in protein kinase A catalytic subunit (PKAc). Using a personalized medicine screening platform, we discovered a Cushing's driver mutation, PKAc-W196G, in ~20% of patient samples analyzed. Proximity proteomics and photokinetic imaging reveal that PKAc
MeSH term(s)	Humans ; Cushing Syndrome/genetics ; A Kinase Anchor Proteins/genetics ; A Kinase Anchor Proteins/metabolism ; Signal Transduction ; Catalytic Domain ; Bias
Chemical Substances	A Kinase Anchor Proteins
Language	English
Publishing date	2024-02-21
Publishing country	United States
Document type	Journal Article
ZDB-ID	2810933-8
ISSN	2375-2548 ; 2375-2548
ISSN (online)	2375-2548
ISSN	2375-2548
DOI	10.1126/sciadv.adl1258
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Article ; Online: Evolutionary and cellular analysis of the 'dark' pseudokinase PSKH2.

Byrne, Dominic P / Shrestha, Safal / Daly, Leonard A / Marensi, Vanessa / Ramakrishnan, Krithika / Eyers, Claire E / Kannan, Natarajan / Eyers, Patrick A

The Biochemical journal

2022 Volume 480, Issue 2, Page(s) 141–160

Abstract: Pseudokinases, so named because they lack one or more conserved canonical amino acids that define their catalytically active relatives, have evolved a variety of biological functions in both prokaryotic and eukaryotic organisms. Human PSKH2 is closely ... ...

Abstract	Pseudokinases, so named because they lack one or more conserved canonical amino acids that define their catalytically active relatives, have evolved a variety of biological functions in both prokaryotic and eukaryotic organisms. Human PSKH2 is closely related to the canonical kinase PSKH1, which maps to the CAMK family of protein kinases. Primates encode PSKH2 in the form of a pseudokinase, which is predicted to be catalytically inactive due to loss of the invariant catalytic Asp residue. Although the biological role(s) of vertebrate PSKH2 proteins remains unclear, we previously identified species-level adaptions in PSKH2 that have led to the appearance of kinase or pseudokinase variants in vertebrate genomes alongside a canonical PSKH1 paralog. In this paper we confirm that, as predicted, PSKH2 lacks detectable protein phosphotransferase activity, and exploit structural informatics, biochemistry and cellular proteomics to begin to characterise vertebrate PSKH2 orthologues. AlphaFold 2-based structural analysis predicts functional roles for both the PSKH2 N- and C-regions that flank the pseudokinase domain core, and cellular truncation analysis confirms that the N-terminal domain, which contains a conserved myristoylation site, is required for both stable human PSKH2 expression and localisation to a membrane-rich subcellular fraction containing mitochondrial proteins. Using mass spectrometry-based proteomics, we confirm that human PSKH2 is part of a cellular mitochondrial protein network, and that its expression is regulated through client-status within the HSP90/Cdc37 molecular chaperone system. HSP90 interactions are mediated through binding to the PSKH2 C-terminal tail, leading us to predict that this region might act as both a cis and trans regulatory element, driving outputs linked to the PSKH2 pseudokinase domain that are important for functional signalling.
MeSH term(s)	Animals ; Humans ; Protein Kinases/metabolism ; Signal Transduction ; Phosphorylation ; Molecular Chaperones/metabolism ; Biological Evolution ; HSP90 Heat-Shock Proteins/metabolism
Chemical Substances	Protein Kinases (EC 2.7.-) ; Molecular Chaperones ; HSP90 Heat-Shock Proteins
Language	English
Publishing date	2022-12-07
Publishing country	England
Document type	Journal Article
ZDB-ID	2969-5
ISSN	1470-8728 ; 0006-2936 ; 0306-3275 ; 0264-6021
ISSN (online)	1470-8728
ISSN	0006-2936 ; 0306-3275 ; 0264-6021
DOI	10.1042/BCJ20220474
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