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CONGENITAL HEMANGIOPERICYTOMA EXTERNAL CAROTID ARTERY LIGATION LIFE-THREATENING HEMORRHAGE

Research Projects

Project Title

X-ray Crystallographic Studies of Poxvirus-Mediated Antagonism of TLR signaling

From

1/10/2005

31/9/2008

Summary

Toll-like receptors (TLRs) are essential components of innate immunity against bacterial and viral pathogens. The ten TLRs in humans recognize broad types of pathogen associated molecular patterns (PAMPs) including nucleic acids and lipopolysaccharides. The signaling cascade is initiated by their intracellular Toll-like/interleukin-1 receptor (TIR) domains which oligomerize and recruit TIR-containing adaptor proteins such as MyD88 to mediate downstream events. Viruses often attenuate immune responses, and recently, vaccinia virus proteins A46R, A52R and K7R have been shown to antagonize TLR signaling pathways. Interestingly, A46R contains a putative TIR domain that binds to MyD88 and blocks TLR activation, in contrast to the TIR domains of TLRs which promote the signaling cascade. The project described here will involve X-ray crystallographic studies of poxvirus proteins A46R, A52R and K7R alone and in complex with their cellular targets in order to understand the molecular basis for antagonism of TLR signaling.

Funding Agency

Science Foundation Ireland

Programme

SFI Frontiers Programme

Person Months

Publications and other Research Outputs

Fram B, Su Y, Truebridge I, Riesselman A.J, Ingraham J.B, Passera A, Napier E, Thadani N.N, Lim S, Roberts K, Kaur G, Stiffler M.A, Marks D.S, Bahl C.D, Khan A.R, Sander C, Gauthier N.P, Simultaneous enhancement of multiple functional properties using evolution-informed protein design, Nature Communications, 15, (1), 2024, Journal Article, PUBLISHED DOI URL

Benarroch Y, Juttukonda L, Sabharwal V, Boateng J, Khan A.R, Yarrington C, Wachman E.M, Taglauer E, Differential Expression of Rab5 and Rab7 Small GTPase Proteins in Placental Tissues From Pregnancies Affected by Maternal Coronavirus Disease 2019, Clinical Therapeutics, 43, (2), 2021, p308 - 318, Journal Article, PUBLISHED DOI URL

Dieter Waschbuesch, Kerryn Berndsen, Pawel Lis, Axel Knebel, Yuko PY Lam, Dario R Alessi & Amir R Khan, Structural basis for the specificity of PPM1H phosphatase for Rab GTPases, EMBO reports, 22: e52675, 2021, p10.15252/embr.202152675 , Journal Article, PUBLISHED DOI URL

Dieter Waschbuesch, Elena Purlyte, Amir R Khan, Dual arginine recognition of LRRK2 phosphorylated Rab GTPases, Biophysical Journal, 120, (9), 2021, p1846 - 1855, Journal Article, PUBLISHED DOI URL

Strofaldi A, Khan A.R, McManus J.J, Surface Exposed Free Cysteine Suppresses Crystallization of Human Î³D-Crystallin, Journal of Molecular Biology, 433, (22), 2021, Journal Article, PUBLISHED DOI URL

Kearney A.M, Khan A.R, Crystal structure of the Rab-binding domain of Rab11 family-interacting protein 2, Acta Crystallographica Section F: Structural Biology Communications, 76, 2020, p357 - 363, Journal Article, PUBLISHED DOI URL

Dieter Waschbusch, Elena Purlyte, Prosenjit Pal, Emma McGrath, Dario R. Alessi, Amir R. Khan, Structural Basis for Rab8a Recruitment of RILPL2 via LRRK2 Phosphorylation of Switch 2, Structure, 28, (1-12), 2020, p10.1016/j.str.2020.01.005 , Notes: [PMID: 32017888 ], Journal Article, PUBLISHED DOI URL URL

Dieter Waschbuesch and Amir R Khan, Phosphorylation of Rab GTPases in the regulation of membrane trafficking, Traffic, 21, (11), 2020, p712 - 719, Review Article, PUBLISHED DOI URL

Garg, R.R. and Jackson, C.B. and Rahman, M.M. and Khan, A.R. and Lewin, A.S. and McFadden, G., Myxoma virus M013 protein antagonizes NF-ÎºB and inflammasome pathways via distinct structural motifs, Journal of Biological Chemistry, 294, (21), 2019, p8480-8489 , Notes: [cited By 0], Journal Article, PUBLISHED DOI

WaschbÃŒsch, D. and HÃŒbel, N. and Ossendorf, E. and Lobbestael, E. and Baekelandt, V. and Lindsay, A.J. and McCaffrey, M.W. and Khan, A.R. and Barnekow, A., Rab32 interacts with SNX6 and affects retromer-dependent Golgi trafficking, PLoS ONE, 14, (1), 2019, Notes: [cited By 0], Journal Article, PUBLISHED TARA - Full Text DOI

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Awards and Honours

Award	Date
Research Grant - SFI Frontiers Programme	2005
Cyril M. Kay Book Prize in Biochemistry University of Alberta	1995
Studentship, Medical Research Council of Canada	1996
Student Travel Award, American Crystallographic Association St. Louis, MI	1997
Finn Wold Travel Award, Eleventh Symposium of the Protein Society, Boston, MA	1997
Dissertation Fellowship, University of Alberta	1998
Graduate Student Poster Prize, CFBS Annual Meeting Edmonton, Alberta	1998
Fellowship, Human Frontiers Science Program	1999
Fellowship, Centre National de la Recherche Scientifique (CNRS), France	2001
Fellowship, Canadian Institutes of Health Research (CIHR)	2002
Research Grant, Scientific Investigator Programme, Science Foundation Ireland	2004

Research Interests

Description Of Research Interests

The experimental goal is determination of structures of Rabs with their effector proteins by X-ray crystallography. The first project will involve Rab6, which regulates the forward and retrograde transport pathways at the level of Golgi membranes. The downstream effects of Rab6 are mediated by Rab6IP1, a 1263-residue Rab6IP1 that contains several novel domains for which there is no structural information in the Protein Data Bank. The second project involves Rab11, which is involved in endocytic recycling processes, as well as endosome-to-Golgi trafficking. One of its effectors is FIP2, which belongs to a family of proteins that contain a conserved C-terminal Rab-binding domain. The structures of these effectors may have novel folds, and the complexes with their respective Rabs are likely to demonstrate novel modes of interaction. In addition, the structure of the complex will enable a generalization of the mechanism of Rab family-mediated signaling, since the domains observed in Rab6IP1 are also found in a variety of other mammalian proteins.

Trinity College Dublin, The University of Dublin

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Dr. Amir Khan

Dr. Amir Khan

Associate Professor (Biochemistry)

Amir.Khan@tcd.ie

3531896 3868

http://people.tcd.ie/amirrafk