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Article ; Online: Molecular insight into the autoinhibition of a master regulator of lipid signalling in human disease.

Burke, John E

2020 Volume 52, Page(s) 102634

MeSH term(s)	Humans ; Lipids ; Signal Transduction
Chemical Substances	Lipids
Language	English
Publishing date	2020-01-22
Publishing country	Netherlands
Document type	Journal Article ; Comment
ZDB-ID	2851331-9
ISSN	2352-3964
ISSN (online)	2352-3964
DOI	10.1016/j.ebiom.2020.102634
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Article ; Online: Structural basis for the conserved roles of PI4KA and its regulatory partners and their misregulation in disease.

Suresh, Sushant / Burke, John E

Advances in biological regulation

2023 Volume 90, Page(s) 100996

Abstract: The type III Phosphatidylinositol 4-kinase alpha (PI4KA) is an essential lipid kinase that is a master regulator of phosphoinositide signalling at the plasma membrane (PM). It produces the predominant pool of phosphatidylinositol 4-phosphate (PI4P) at ... ...

Abstract	The type III Phosphatidylinositol 4-kinase alpha (PI4KA) is an essential lipid kinase that is a master regulator of phosphoinositide signalling at the plasma membrane (PM). It produces the predominant pool of phosphatidylinositol 4-phosphate (PI4P) at the PM, with this being essential in lipid transport and in regulating the PLC and PI3K signalling pathways. PI4KA is essential and is highly conserved in all eukaryotes. In yeast, the PI4KA ortholog stt4 predominantly exists as a heterodimer with its regulatory partner ypp1. In higher eukaryotes, PI4KA instead primarily forms a heterotrimer with a TTC7 subunit (ortholog of ypp1) and a FAM126 subunit. In all eukaryotes PI4KA is recruited to the plasma membrane by the protein EFR3, which does not directly bind PI4KA, but instead binds to the TTC7/ypp1 regulatory partner. Misregulation in PI4KA or its regulatory partners is involved in myriad human diseases, including loss of function mutations in neurodevelopmental and inflammatory intestinal disorders and gain of function in human cancers. This review describes an in-depth analysis of the structure function of PI4KA and its regulatory partners, with a major focus on comparing and contrasting the differences in regulation of PI4KA throughout evolution.
MeSH term(s)	Humans ; Cell Membrane/genetics ; Cell Membrane/metabolism ; Phosphatidylinositols/metabolism ; Proteins/metabolism ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae/metabolism ; Signal Transduction ; Phosphotransferases (Alcohol Group Acceptor)/chemistry ; Phosphotransferases (Alcohol Group Acceptor)/metabolism ; Animals
Chemical Substances	Phosphatidylinositols ; Proteins ; phosphatidylinositol phosphate 4-kinase (EC 2.7.1.67) ; Phosphotransferases (Alcohol Group Acceptor) (EC 2.7.1.-)
Language	English
Publishing date	2023-11-10
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2667413-0
ISSN	2212-4934 ; 2212-4926
ISSN (online)	2212-4934
ISSN	2212-4926
DOI	10.1016/j.jbior.2023.100996
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Article ; Online: Dynamic structural biology at the protein membrane interface.

Burke, John E

The Journal of biological chemistry

2019 Volume 294, Issue 11, Page(s) 3872–3880

Abstract: Since I started doing scientific research, I've been fascinated by the interplay of protein structure and dynamics and how they together mediate protein function. A particular area of interest has been in understanding the mechanistic basis of how lipid- ... ...

Abstract	Since I started doing scientific research, I've been fascinated by the interplay of protein structure and dynamics and how they together mediate protein function. A particular area of interest has been in understanding the mechanistic basis of how lipid-signaling enzymes function on membrane surfaces. In this award lecture article, I will describe my laboratory's studies on the structure and dynamics of lipid-signaling enzymes on membrane surfaces. This is important, as many lipid-signaling enzymes are regulated through dynamic regulatory mechanisms that control their enzymatic activity. This article will discuss my continued enthusiasm in using a synergistic application of hydrogen-deuterium exchange MS (HDX-MS) with other structural biology techniques to probe the mechanistic basis for how membrane-localized signaling enzymes are regulated and how these approaches can be used to understand how they are misregulated in disease. I will discuss specific examples of how we have used HDX-MS to study phosphoinositide kinases and the protein kinase Akt. An important focus will be on a description of how HDX-MS can be used as a powerful tool to optimize the design of constructs for X-ray crystallography and EM. The use of a diverse toolbox of biophysical methods has revealed novel insight into the complex and varied regulatory networks that control the function of lipid-signaling enzymes and enabled unique insight into the mechanics of membrane recruitment.
MeSH term(s)	Crystallography, X-Ray ; Deuterium Exchange Measurement ; Humans ; Mass Spectrometry ; Membrane Proteins/chemistry ; Membrane Proteins/metabolism ; Models, Molecular ; Phosphatidylinositol 3-Kinases/chemistry ; Phosphatidylinositol 3-Kinases/metabolism ; Protein Conformation ; Proto-Oncogene Proteins c-akt/chemistry ; Proto-Oncogene Proteins c-akt/metabolism
Chemical Substances	Membrane Proteins ; Phosphatidylinositol 3-Kinases (EC 2.7.1.-) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1)
Language	English
Publishing date	2019-01-28
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.AW118.003236
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Article ; Online: PI4KA and PIKfyve: Essential phosphoinositide signaling enzymes involved in myriad human diseases.

Barlow-Busch, Isobel / Shaw, Alexandria L / Burke, John E

Current opinion in cell biology

2023 Volume 83, Page(s) 102207

Abstract: Lipid phosphoinositides are master regulators of multiple cellular functions. Misregulation of the activity of the lipid kinases that generate phosphoinositides is causative of human diseases, including cancer, neurodegeneration, developmental disorders, ...

Abstract	Lipid phosphoinositides are master regulators of multiple cellular functions. Misregulation of the activity of the lipid kinases that generate phosphoinositides is causative of human diseases, including cancer, neurodegeneration, developmental disorders, immunodeficiencies, and inflammatory disease. This review will present a summary of recent discoveries on the roles of two phosphoinositide kinases (PI4KA and PIKfyve), which have emerged as targets for therapeutic intervention. Phosphatidylinositol 4-kinase alpha (PI4KA) generates PI4P at the plasma membrane and PIKfyve generates PI(3,5)P
MeSH term(s)	Humans ; Cell Membrane/metabolism ; Lysosomes/metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Phosphatidylinositols/metabolism ; Signal Transduction
Chemical Substances	Phosphatidylinositol 3-Kinases (EC 2.7.1.-) ; Phosphatidylinositols ; phosphatidylinositol phosphate 4-kinase (EC 2.7.1.67) ; PIKFYVE protein, human (EC 2.7.1.137)
Language	English
Publishing date	2023-07-14
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1026381-0
ISSN	1879-0410 ; 0955-0674
ISSN (online)	1879-0410
ISSN	0955-0674
DOI	10.1016/j.ceb.2023.102207
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Article ; Online: Cognitive function 10 years after adolescent bariatric surgery.

Burke, Erin / Jenkins, Todd / Boles, Richard E / Mitchell, James E / Inge, Thomas / Gunstad, John

Surgery for obesity and related diseases : official journal of the American Society for Bariatric Surgery

2024

Abstract: ... executive function (e.g., Continuous Performance Test - Reaction Time 30%; Maze Errors - Overrun 30%), and 53.5% met ... up (e.g., 20 yr after surgery), and identify underlying mechanisms and mitigation strategies. ...

Abstract	Background: Adolescent bariatric surgery produces substantial weight loss and reduction of medical co-morbidities. Research in adult samples shows improved cognitive function postoperatively, although much less is known about the potential cognitive benefits of bariatric surgery in adolescents-especially at extended follow-up. Objective: Examine cognitive function 10 years after adolescent bariatric surgery. Setting: University hospital. Methods: A total of 99 young adults who underwent bariatric surgery as adolescents completed a computerized cognitive test battery as part of a larger 10-year postoperative assessment. All had been long-term participants in the Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS) study. Results: Cognitive dysfunction was prevalent on tests of attention and executive function (e.g., Continuous Performance Test - Reaction Time 30%; Maze Errors - Overrun 30%), and 53.5% met research criteria for mild cognitive impairment (MCI). Modified Poisson regression with robust error variance revealed participants with preoperative hypertension and those completing Roux-en-Y gastric bypass were more likely to meet criteria for MCI at 10-year follow-up. Conclusions: The current findings indicate that cognitive deficits are common 10 years after bariatric surgery. Additional studies are needed to clarify possible cohort effects, determine whether these cognitive deficits persist to even later follow-up (e.g., 20 yr after surgery), and identify underlying mechanisms and mitigation strategies.
Language	English
Publishing date	2024-01-24
Publishing country	United States
Document type	Journal Article
ZDB-ID	2274243-8
ISSN	1878-7533 ; 1550-7289
ISSN (online)	1878-7533
ISSN	1550-7289
DOI	10.1016/j.soard.2024.01.008
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Article ; Online: Trends in observation stays for Medicare beneficiaries with and without Alzheimer's disease and related dementias.

Burke, Laura G / Burke, Ryan C / Duggan, Ciara E / Figueroa, Jose F / Boltz, Marie / Fick, Donna M / Orav, E John / Marcantonio, Edward R

Journal of the American Geriatrics Society

2024

Abstract: Background: There has been a marked rise in the use of observation care for Medicare beneficiaries visiting the emergency department (ED) in recent years. Whether trends in observation use differ for people with Alzheimer's disease and Alzheimer's ... ...

Abstract	Background: There has been a marked rise in the use of observation care for Medicare beneficiaries visiting the emergency department (ED) in recent years. Whether trends in observation use differ for people with Alzheimer's disease and Alzheimer's disease-related dementias (AD/ADRD) is unknown. Methods: Using a national 20% sample of Medicare beneficiaries ages 68+ from 2012 to 2018, we compared trends in ED visits and observation stays by AD/ADRD status for beneficiaries visiting the ED. We then examined the degree to which trends differed by nursing home (NH) residency status, assigning beneficiaries to four groups: AD/ADRD residing in NH (AD/ADRD+ NH+), AD/ADRD not residing in NH (AD/ADRD+ NH-), no AD/ADRD residing in NH (AD/ADRD- NH+), and no AD/ADRD not residing in NH (AD/ADRD- NH-). Results: Of 7,489,780 unique beneficiaries, 18.6% had an AD/ADRD diagnosis. Beneficiaries with AD/ADRD had more than double the number of ED visits per 1000 in all years compared to those without AD/ADRD and saw a faster adjusted increase over time (+26.7 vs. +8.2 visits/year; p < 0.001 for interaction). The annual increase in the adjusted proportion of ED visits ending in observation was also greater among people with AD/ADRD (+0.78%/year, 95% CI 0.77-0.80%) compared to those without AD/ADRD (+0.63%/year, 95% CI 0.59-0.66%; p < 0.001 for interaction). Observation utilization was greatest for the AD/ADRD+ NH+ population and lowest for the AD/ADRD- NH- population, but the AD/ADRD+ NH- group saw the greatest increase in observation stays over time (+15.4 stays per 1000 people per year, 95% CI 15.0-15.7). Conclusions: Medicare beneficiaries with AD/ADRD have seen a disproportionate increase in observation utilization in recent years, driven by both an increase in ED visits and an increase in the proportion of ED visits ending in observation.
Language	English
Publishing date	2024-03-28
Publishing country	United States
Document type	Journal Article
ZDB-ID	80363-7
ISSN	1532-5415 ; 0002-8614
ISSN (online)	1532-5415
ISSN	0002-8614
DOI	10.1111/jgs.18890
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Article ; Online: Molecular insight into the autoinhibition of a master regulator of lipid signalling in human disease

John E. Burke

EBioMedicine, Vol 52, Iss , Pp - (2020)

2020

Keywords	Medicine ; R ; Medicine (General) ; R5-920
Language	English
Publishing date	2020-02-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Structural Basis for Regulation of Phosphoinositide Kinases and Their Involvement in Human Disease.

Burke, John E

Molecular cell

2018 Volume 71, Issue 5, Page(s) 653–673

Abstract: Lipid phosphoinositides play fundamental roles in virtually all pathways that control a cell's decision to grow, move, divide, and die. Because of this, kinases that phosphorylate phosphoinositide lipids are critically involved in myriad essential ... ...

Abstract	Lipid phosphoinositides play fundamental roles in virtually all pathways that control a cell's decision to grow, move, divide, and die. Because of this, kinases that phosphorylate phosphoinositide lipids are critically involved in myriad essential functions including growth, development, and membrane trafficking. The misregulation of phosphoinositide kinases is critical in human diseases, including cancer, primary immunodeficiencies, and developmental disorders. Phosphoinositide kinases also play a role in mediating bacterial and viral infections for many potent human pathogens. Furthermore, inhibitors of parasite phosphoinositide kinases are in development as therapies for both malaria and cryptosporidiosis. Therefore, understanding how phosphoinositide kinases are regulated has implications for the treatment of many devastating human diseases. Recent structures of phosphoinositide kinases have revealed unique molecular insight into their regulation. This review will summarize our current molecular knowledge on phosphoinositide kinase regulation, and how this information is being used to generate novel small molecule inhibitors as potential therapeutics.
MeSH term(s)	1-Phosphatidylinositol 4-Kinase/metabolism ; Animals ; Humans ; Phosphatidylinositols/metabolism ; Signal Transduction/physiology
Chemical Substances	Phosphatidylinositols ; 1-Phosphatidylinositol 4-Kinase (EC 2.7.1.67)
Language	English
Publishing date	2018-09-07
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1415236-8
ISSN	1097-4164 ; 1097-2765
ISSN (online)	1097-4164
ISSN	1097-2765
DOI	10.1016/j.molcel.2018.08.005
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Article ; Online: Precision Targeting of Mutant PI3Kα in Cancer by Selective Degradation.

Vanhaesebroeck, Bart / Burke, John E / Madsen, Ralitsa R

Cancer discovery

2022 Volume 12, Issue 1, Page(s) 20–22

Abstract: ... ...

Abstract	PIK3CA
MeSH term(s)	Class I Phosphatidylinositol 3-Kinases/genetics ; Humans ; Neoplasms/drug therapy ; Neoplasms/genetics ; Protein Kinase Inhibitors/pharmacology ; Protein Kinase Inhibitors/therapeutic use
Chemical Substances	Protein Kinase Inhibitors ; Class I Phosphatidylinositol 3-Kinases (EC 2.7.1.137)
Language	English
Publishing date	2022-09-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Comment
ZDB-ID	2625242-9
ISSN	2159-8290 ; 2159-8274
ISSN (online)	2159-8290
ISSN	2159-8274
DOI	10.1158/2159-8290.CD-21-1411
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Article ; Online: Investigating how intrinsically disordered regions contribute to protein function using HDX-MS.

Parson, Matthew A H / Jenkins, Meredith L / Burke, John E

Biochemical Society transactions

2022

Abstract: A large amount of the human proteome is composed of highly dynamic regions that do not adopt a single static conformation. These regions are defined as intrinsically disordered, and they are found in a third of all eukaryotic proteins. They play ... ...

Abstract	A large amount of the human proteome is composed of highly dynamic regions that do not adopt a single static conformation. These regions are defined as intrinsically disordered, and they are found in a third of all eukaryotic proteins. They play instrumental roles in many aspects of protein signaling, but can be challenging to characterize by biophysical methods. Intriguingly, many of these regions can adopt stable secondary structure upon interaction with a variety of binding partners, including proteins, lipids, and ligands. This review will discuss the application of Hydrogen-deuterium exchange mass spectrometry (HDX-MS) as a powerful biophysical tool that is particularly well suited for structural and functional characterization of intrinsically disordered regions in proteins. A focus will be on the theory of hydrogen exchange, and its practical application to identify disordered regions, as well as characterize how they participate in protein-protein and protein-membrane interfaces. A particular emphasis will be on how HDX-MS data can be presented specifically tailored for analysis of intrinsically disordered regions, as well as the technical aspects that are critical to consider when designing HDX-MS experiments for proteins containing intrinsically disordered regions.
Language	English
Publishing date	2022-12-01
Publishing country	England
Document type	Journal Article
ZDB-ID	184237-7
ISSN	1470-8752 ; 0300-5127
ISSN (online)	1470-8752
ISSN	0300-5127
DOI	10.1042/BST20220206
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