Shehab Ismail - Structural Biology of Cilia

Introduction

ismail s

The primary cilium is a microtubule-based sensory organelle that is present on almost all cell types in the body. The assembly of cilia is tightly synchronised with cell cycle and coordinates several signalling pathways such as the Wnt and Hedgehog pathways, both of which are therapeutic targets for cancer. Defects in the structure or function of cilia result in a copious spectrum of diseases collectively called ciliopathies. Phenotypes include retinal degeneration, renal cysts, intellectual disabilities, obesity, polydactyly and infertility.

Concentrating signalling proteins and receptors inside the cilium is key to its function. Nevertheless the cilium, unlike other organelles, is not separated from the cell body by a membrane barrier and the molecular mechanism for regulating ciliary targeting and access of relevant protein to cilia is elusive. A combination of ciliary targeting and the existence of a diffusion barrier that is found at the base of the cilium are believed to play a role in this process. In our group we try to unravel the regulation of ciliary access by using an interdisciplinary approach where we combine structural biology, biochemistry and cell biology.

Lab Report

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Key Recent Publications

Ismail SA. A GDI/GDF like system for sorting and shuttling ciliary proteins. Small GTPases, 2016 Aug, Epub ahead of print

Fansa EK, Kösling SK, Zent E, Wittinghofer A, Ismail S. PDE6δ-mediated sorting of INPP5E into the cilium is determined by cargo-carrier affinity. Nat Commun 7, 11366, 2016. doi: 10.1038/ncomms11366

Zimmermann G*, Papke B*, Ismail S*, Vartak N, Chandra A, Hoffmann M, Hahn SA, Triola G, Wittinghofer A, Bastiaens PIH, Waldmann H. Small Molecule Inhibition of the Kras-PDEδ Interaction Impairs Oncogenic Kras Signaling. Nature 497:638-42, 2013 *authors contributed equally

Wätzlich D, Vetter I, Gotthardt K, Miertzschke M, Chen Y-X, Wittinghofer A, Ismail S. The interplay between RPGR, PDEδ and Arl2/3 regulates the ciliary targeting of farnesylated cargo. EMBO Rep. 14:465-72, 2013

Ismail SA, Chen Y-X, Miertzschke M, Vetter I, Carolin K, Wittinghofer A. Structural basis for Arl3-specific release of myristoylated ciliary cargo from UNC119. EMBO J. 31:4085-94, 2012

Ismail SA, Chen Y-X, Rusinova A, Chandra A, Bierbaum M, Gremer L, Triola G, Waldmann H, Bastiaens PIH, Wittinghofer A. Arl2 and Arl3-GTP regulate a GDI-like transport system for farnesylated cargo. Nat Chem Biol. 7:942-9, 2011

Ismail SA, Vetter IR, Sot B, Witinghofer A. The structure of an Arf-ArfGAP complex reveals a Ca2+ regulatory mechanism. Cell 141:812-21, 2010

Biography

Education and qualifications

2005: PhD, University of Tennessee/St Jude Children's Research Hospital, USA
2000: BSc, Pharmacy, Cairo University, Egypt

Appointments

2014-present: Junior Group Leader, CRUK Beatson Institute
2007-2014: Postdoctoral Fellow, Department of Structural Biology, Max-Planck-Institute, Dortmund, Germany, with Prof Alfred Wittinghofer
2006-2007: Lecturer, The German University in Cairo, Egypt
2005-2006: Postdoctoral Fellow, Structural Genomics Consortium, University of Toronto, Canada, with Dr Hee Won Park

Honours and awards

Alexander Von Humboldt Fellowship, 2007-2009

Recent Publications

2017

Reid SE, Kay EJ, Neilson LJ, Henze AT, Serneels J, McGhee EJ, Dhayade S, Nixon C, Mackey JB, Santi A, Swaminathan K, Athineos D, Papalazarou V, Patella F, Román-Fernández Á, ElMaghloob Y, Hernandez-Fernaud JR, Adams RH, Ismail S, Bryant DM, Salmeron-Sanchez M, Machesky LM, Carlin LM, Blyth K, Mazzone M, Zanivan S.Tumor matrix stiffness promotes metastatic cancer cell interaction with the endothelium. EMBO J EMBO J 36: 2373-89, 2017

Gray CH, Konczal J, Mezna M, Ismail S, Bower J, Drysdale M. A fully automated procedure for the parallel, multidimensional purification and nucleotide loading of the human GTPases KRas, Rac1 and RalB. Protein Expr Purif 132: 75-84, 2017

Martín-Gago P, Fansa EK, Klein CH, Murarka S, Janning P, Schürmann M, Metz M, Ismail S, Schultz-Fademrecht C, Baumann M, Bastiaens PI, Wittinghofer A, Waldmann H. A PDE6δ-KRas Inhibitor Chemotype with up to Seven H-Bonds and Picomolar Affinity that Prevents Efficient Inhibitor Release by Arl2. Angew Chem Int Ed Engl 56: 2423-8, 2017

2016

Fansa EK, Kösling SK, Zent E, Wittinghofer A, Ismail S. PDE6δ-mediated sorting of INPP5E into the cilium is determined by cargo-carrier affinity. Nat Commun 7, 11366, 2016

Murarka S, Martín-Gago P, Schultz-Fademrecht C, Al Saabi A, Baumann M, Fansa E, Ismail S, Nussbaumer P, Wittinghofer A, Waldmann H. Development of Pyridazinone Chemotypes Targeting the PDEδ Prenyl Binding Site. Chemistry, 2016 Nov 3, doi: 10.1002/chem.201603222

Papke B, Murarka S, Vogel HA, Martín-Gago P, Kovacevic M, Truxius DC, Fansa EK, Ismail S, Zimmermann G, Heinelt K, Schultz-Fademrecht C, Al Saabi A, Baumann M, Nussbaumer P, Wittinghofer A, Waldmann H, Bastiaens PI. Identification of pyrazolopyridazinones as PDEδ inhibitors. Nat Commun 7, 11360, 2016

Ismail SA. A GDI/GDF like system for sorting and shuttling ciliary proteins. Small GTPases, 2016 Aug 3: 1-4, 2016

Stephen LA, Ismail S. Shuttling and sorting lipid-modified cargo into the cilia. Biochem Soc Trans 44, 1273-80, 2016

2015

Fansa EK, O'Reilly N, Ismail S, Wittinghofer A. The N- and C-terminal ends of RPGR can bind to PDE6d. EMBO Reports 16, 1583-5, 2015

Kapoor S, Fansa EK, Möbitz S, Ismail SA, Winter R, Wittinghofer A, Weise K. Effect of the N-Terminal Helix and Nucleotide Loading on the Membrane and Effector Binding of Arl2/3. Biophys J 109: 1619-29, 2015

2014

Bravo-Rodriguez K, Ismail-Ali AF, Klopries S, Kushnir S, Ismail S, Fansa EK, Wittinghofer A, Schulz F, Sanchez-Garcia E. Predicted Incorporation of Non-native Substrates by a Polyketide Synthase Yields Bioactive Natural Product Derivatives. ChemBioChem 15: 1991-7, 2014

Suladze S, Ismail S, Winter R. Thermodynamic, dynamic and solvational properties of PDEdelta binding to farnesylated cystein: a model study for uncovering the molecular mechanism of PDEdelta interaction with prenylated proteins. J Phys Chem B 118: 966-75, 2014

Zimmermann G, Schultz-Fademrecht C, Kuchler P, Murarka S, Ismail S, Triola G, Nussbaumer P, Wittinghofer A, Waldmann H. Structure Guided Design and Kinetic Analysis of Highly Potent Benzimidazole Inhibitors Targeting the PDEdelta Prenyl Binding Site. J Med Chem 57: 5435-48, 2014

2013

Zimmermann G*, Papke B*, Ismail S*, Vartak N, Chandra A, Hoffmann M, Hahn SA, Triola G, Wittinghofer A, Bastiaens PIH, Waldmann H. Small Molecule Inhibition of the Kras-PDEδ Interaction Impairs Oncogenic Kras Signaling. Nature 497:638-42, 2013 *authors contributed equally

Wätzlich D, Vetter I, Gotthardt K, Miertzschke M, Chen Y-X, Wittinghofer A, Ismail S. The interplay between RPGR, PDEδ and Arl2/3 regulates the ciliary targeting of farnesylated cargo. EMBO Rep. 14:465-72, 2013

2012

Ismail SA, Chen Y-X, Miertzschke M, Vetter I, Carolin K, Wittinghofer A. Structural basis for Arl3-specific release of myristoylated ciliary cargo from UNC119. EMBO J. 31:4085-94, 2012

Lab Members

ismail group

Post-docs

Louise Stephen
Tomas Yelland

Scientific Officer

Michael McIlwraith

PhD Student

Yasmin ElMaghloob

Research

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Seminars

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