CFTR, the odd ABC transporter responsible for cystic fibrosis Jue - PowerPoint PPT Presentation

Dec 29, 2022 •288 likes •676 views

CFTR, the odd ABC transporter responsible for cystic fibrosis Jue Chen Laboratory of Membrane Biology and Biophysics Cystic Fibrosis is a genetic disease cftr Picture credit: Bruce Blaus CFTR, an odd ABC transporter Typical ABC transporters:

CFTR, the odd ABC transporter responsible for cystic fibrosis Jue Chen Laboratory of Membrane Biology and Biophysics
Cystic Fibrosis is a genetic disease cftr Picture credit: Bruce Blaus
CFTR, an odd ABC transporter Typical ABC transporters: ATP-powered pumps CFTR: an ATP-gated anion channel Phosphorylation
Phosphorylation gates the CFTR channel
Phosphorylation also regulates ATPase activity Zhe Zhang
Cryo-EM analysis of CFTR Zhe Zhang
Cryo-EM analysis of CFTR • Movie alignment and exposure filter -- Unblur : Grant & Grigorieff, eLIFE, 2015 • Particle alignment -- alignparts_lmbfgs : Rubinstein & Brubaker, J Struct Biol. 2014 • Estimate defocus parameters -- CTFFND4 : Rohou & Grigorieff, J Struct Biol. (2015) • Particle picking and subsequent processing -- Relion : Scheres, J Struct Biol. 2015 • Final runs of 3D refinement -- Frealign : Lyumkis & Grigorieff, J Struct Biol. 2013
Cryo-EM analysis of zebrafish CFTR
Cryo-EM analysis of zebrafish CFTR
Cryo-EM analysis of zebrafish CFTR
Zebrafish CFTR
Human CFTR Fangyu Liu and Zhe Zhang
The ion conduction pathway
Positively charged residues Reviewed in Linsdell, 2017
Anion selectivity / e / e
Selectivity
Towards an open channel conformation David C. Gadsby
Cryo-EM analysis of phosphorylated CFTR
Cryo-EM analysis of phosphorylated CFTR
Cryo-EM analysis of phosphorylated CFTR
Cryo-EM analysis of phosphorylated CFTR
R domain prevents NBD dimerization Dephosphorylated ATP-free
R domain prevents NBD dimerization Phosphorylated ATP-bound
Conformational changes
Conformational changes
Local conformations control ion access
Flickering David C. Gadsby
The CFTR gating cycle
The CFTR gating cycle
Cystic Fibrosis-causing mutations • >1000 mutations in CFTR • 272 mutations causing CF • 53 missense mutations at 46 positions
Cystic Fibrosis-causing mutations
Pore construction mutants
Folding mutants
ATPase site mutants
NBD/TMD interface mutants
NBD/TMD interface mutants
Cystic Fibrosis-causing mutations
Acknowledgment EM Mentors CFTR project • Tom Walz • Zongli Li Zhe Zhang • Rich Hite • Nikolaus Grigorieff Fangyu Liu • Tim Grant • Alexis Rohou David C. Gadsby Staff at RU and Janelia • Mark Ebrahim • Johanna Sotiris • Zhiheng Yu • Chuang Hong • Rick Huang

Recommend

the Effects of QR-010 on Nasal Potential Difference in Subjects With Cystic Fibrosis with the

Proof of Concept Study to Demonstrate the Effects of QR-010 on Nasal Potential Difference in Subjects With Cystic Fibrosis with the F508del CFTR Mutation Noreen R Henig, MD JP Clancy, MD Chief Development Officer Professor of Pediatrics

555 views • 16 slides

Cystic Pancreatic Neoplasms Diagnosis of Cystic and Intraductal Tumors of the Pancreas

Cystic Pancreatic Neoplasms Diagnosis of Cystic and Intraductal Tumors of the Pancreas Fundamentally cystic neoplasms Serous cystic neoplasms Mucinous cystic neoplasms Secondarily cystic neoplasms David S. Klimstra, M.D. Solid

700 views • 33 slides

1 2 Key Points Linkage analysis provides evidence for the existence of a single CFTR locus

1 2 Key Points Linkage analysis provides evidence for the existence of a single CFTR locus on human chromosome 7 (region q31) 1 There are more than 1900 known mutations of the CFTR gene 2 Of the mutations reported so far, 140 meet

591 views • 35 slides

Is it possible to define a core set that should be evaluated in all studies? No disclosures

Is it possible to define a core set that should be evaluated in all studies? No disclosures ESPGHAN Cystic Fibrosis Working group Clinical outcome measures (in vivo or ex vivo) CFTR function testing Nasal potential Organoid

821 views • 43 slides

Changes in the management of children with Cystic Fibrosis Caroline Murphy & Deirdre

Changes in the management of children with Cystic Fibrosis Caroline Murphy & Deirdre ODonovan CF Nurses What Is Cystic Fibrosis? Cystic fibrosis (CF) is an inherited chronic disease that primarily affects the lungs and digestive

410 views • 19 slides

Pancreatic Mass: Solid or Cystic? Solid Pancreatic masses Cystic pancreatic masses -

Workshop -ROSE in EUS guided FNA of Pancreatic Lesions Guys Hospital, London, 16 April 2018 Laxmi Batav Imperial College NHS Trust Pancreatic Mass: Solid or Cystic? Solid Pancreatic masses Cystic pancreatic masses - Ductal

332 views • 11 slides

Bile salt synthesis Hepatic Transporter Proteins involved in Bile Formation Basolateral membrane

Bile salt synthesis Hepatic Transporter Proteins involved in Bile Formation Basolateral membrane transporter proteins fx: NTCP uptake of bile salts OATP bulky organic anions Canalicular membrane transporter proteins fx: BSEP ATP dependent

389 views • 34 slides

CYSTIC FIBROSIS Lynne M. Quittell, M.D. Director, CF Center Columbia University What is Cystic

CYSTIC FIBROSIS Lynne M. Quittell, M.D. Director, CF Center Columbia University What is Cystic Fibrosis? Chronic, progressive and life limiting autosomal recessive genetic disease characterized by chronic respiratory disease, pancreatic

692 views • 23 slides

What is Cystic Fibrosis- Related Diabetes Combination of insulin deficiency and insulin

Cystic Fibrosis-Related Diabetes Shayne Dougherty MSN, CRNP Diabetes Nurse Practitioner/CFRD Specialist Division of Pediatric Endocrinology & Diabetes Childrens Hospital of Philadelphia What is Cystic Fibrosis- Related Diabetes

456 views • 19 slides

Emerging Networks: Learning from Successful Networks Tim Lee European Cystic Fibrosis Society

Emerging Networks: Learning from Successful Networks Tim Lee European Cystic Fibrosis Society Clinical Trials Network Enpr-EMA Annual Workshop March 22 nd 2012 Cystic Fibrosis Rare: 0.74 per 10,000 30,000 in EU Median survival 26-28

145 views • 11 slides

1 2 3 Cystic fibrosisrelated diabetes (CFRD) is a distinct clinical entity from type 1

1 2 3 Cystic fibrosisrelated diabetes (CFRD) is a distinct clinical entity from type 1 or type 2 diabetes, affecting approximately 35% of the cystic fibrosis (CF) population, with a peak age of onset in the 20-to 24-year range

858 views • 49 slides

E way Bill To be generated on the ewaybill.nic.in before movement of goods Transporter need

E way Bill To be generated on the ewaybill.nic.in before movement of goods Transporter need to carry along with goods Seamless interstate movement of goods A tool to curb parallel Economy Boost Revenue by 15 20% Its

773 views • 11 slides

Cake Transporter Market Retail Bakeries $2.9 billion retail

Cake Transporter Market Retail Bakeries $2.9 billion retail bakery products shipped in 2008 Wedding Cake Industry TransportaAon costs $50-$100

311 views • 10 slides

I. Barry HOLLAND University PARIS-SUD, France Some History of the ABC Transporter Super Family

The ABC superfamily and a simple and successful way to organize a meeting to discuss them 10 th Anniversary of the Franco-Belge ABC meeting in Brussels I. Barry HOLLAND University PARIS-SUD, France Some History of the ABC Transporter Super

401 views • 7 slides

A personalised approach to Cystic Fibrosis Professor Adam Jaffe @HISA_HIC #HIC18 School of

A personalised approach to Cystic Fibrosis Professor Adam Jaffe @HISA_HIC #HIC18 School of Womens and Childrens Health A personalised approach to Cystic Fibrosis Adam Jaffe John Beveridge Professor of Paediatrics Respiratory

808 views • 39 slides

CAT-5571 as a novel therapeutic that reduces infection and controls inflammation in cystic

CAT-5571 as a novel therapeutic that reduces infection and controls inflammation in cystic fibrosis Feng Liu 1 , Kathrin Krause 2 , Amal Amer 2 , Luanne Hall-Stoodley 2 , John F. Reilly 1 and Andrew J. Nichols 1 EPS1.05 1 Catabasis

192 views • 4 slides

A Phase 2 Study of the Safety, Pharmacokinetics and Efficacy of Anabasum (JBT-101) in Cystic

A Phase 2 Study of the Safety, Pharmacokinetics and Efficacy of Anabasum (JBT-101) in Cystic Fibrosis (CF) James F. Chmiel, M.D., M.P.H., J. Stuart Elborn M.D., Scott Constantine M.S., Barbara White M.D., for the JBT101-CF-001 Investigators 1

428 views • 13 slides

Serotonin Transporter Gene Polymorphism, Response Inhibition, Auditory Attention and Emotional

Serotonin Transporter Gene Polymorphism, Response Inhibition, Auditory Attention and Emotional Variations: An investigation of the link between behaviors and genotypic polymorphism. FREEMAN, N., PHD, GRABER, J.R., PERKINS, J.N., RUDKIN, R.L.

248 views • 20 slides

Acne Papulopustular Topicals okay Cystic, scarring, keloidal p.o. antibiotics

Common Dermatologic Conditions in Women Toby Maurer, MD University of California, San Francisco No Disclosures Acne Papulopustular Topicals okay Cystic, scarring, keloidal p.o. antibiotics Accutane Topicals BP 5% gel (10%

406 views • 23 slides

Gas Operational Forum London Radisson Grafton 27 th September 2018 Gas Prices, Transporter

Gas Operational Forum London Radisson Grafton 27 th September 2018 Gas Prices, Transporter Actions and Neutrality September 2018 Summary Report YEAR TO DATE PERCENTAGES AGAINST BUYS AND SELLS FOR JUNE - AUGUST (2017 - 2018) Jun-17 Jun-18

748 views • 29 slides

sodium-dependent bile acid transporter inhibitor maralixibat in children with Alagille syndrome:

A long-term phase 2 safety and efficacy study of the apical sodium-dependent bile acid transporter inhibitor maralixibat in children with Alagille syndrome: preliminary results from the IMAGINE study Richard J Thompson King's College London,

408 views • 15 slides

sodium-dependent bile acid transporter inhibitor maralixibat in children with progressive familial

Phase 2 open-label efficacy and safety study of the apical sodium-dependent bile acid transporter inhibitor maralixibat in children with progressive familial intrahepatic cholestasis: 48-week interim efficacy analysis Richard J Thompson King's

317 views • 18 slides

Team Kevin Thompson EE Responsible for circuit design Sam Foster EE Responsible

Team Kevin Thompson EE Responsible for circuit design Sam Foster EE Responsible for code which manages power distribution on the heated surface Craig Cogdill CompE Responsible for graphical user interface Stanley Nestler

606 views • 17 slides

WHAT DO WE MEAN BY RESPONSIBLE SOURCING? TO WHOM ARE WE RESPONSIBLE? Employees Customers

WHAT DO WE MEAN BY RESPONSIBLE SOURCING? TO WHOM ARE WE RESPONSIBLE? Employees Customers Stakeholders Society A child living in close proximity to a gem-mining district is likely to care considerably less about whether a

841 views • 16 slides