Ph.D, The Rockefeller University
One of the great quandaries of our age is that despite all our scientific progress, our attempts to improve human lives often seems high-risk, time-intensive and expensive. The genetic code has been deciphered, thousands of genomes have been sequenced, and most protein folds are now known. However, our understanding of how dynamic organelles and living cells are formed is at its infancy, and more effective drug molecules for addressing the unmet needs of patients are ever-more costly to design and deliver.
To address the gaps, we focus on three areas:
- To move from the genetic code to cellular organization, we are determining how proteins recognize lipids and reshape membranes. Our successes include the elucidation of how FYVE and PX domains bind the phosphoinositol 3-phosphate lipids found on endosomes, and how PH domains recognize phosphoinositol 4-phosphate on Golgi membranes. Working with collaborators we also discovered how the Bro1 domain recruits proteins to late endosomes, and developed predictive “MODA” software for identifying novel membrane binding surfaces on virtually any protein structure. Ultimately we hope to decipher the phospholipid code whereby proteins recognize complex membrane surfaces and shape dynamic organelle structures.
- To understand disease mechanisms we study oncogene products, critical pathways used by viral and bacterial pathogens, and proteins exhibiting mutations that correlate with debilitating human disease. Our targets include GTPases, kinases and phosphatases and their regulatory domains, tetraspanins including the CD81 receptor for Hepatitis C virus, and desmosomal proteins that mediate cell adhesion and cytoskeletal attachment. By elucidating the structures, dynamics and interactions of these systems, we hope to expose new opportunities for therapeutic intervention.
- To reduce the cost of drug discovery and open up entirely new target areas, we are developing tools for the research community. Libraries of molecules including biological signals and drug fragments have been assembled to identify novel pockets and starting points for efficient lead discovery. Biophysical methods including nuclear magnetic resonance spectroscopy are being harnessed to identify hits and binding modes. Polymers are being used to solubilize and study challenging membrane protein targets. These tools are shared freely on-line, via open access facilities like NANUC, and through collaborative projects where further development is needed.
Our lab’s ethos is team-based and collaborative, and involves international consortia and funding from across the world. We partner with industry to address global challenges including tackling novel targets and cancers lacking effective cures, we work with business to develop new products, and engage with leaders to inform policy and spur innovation.
Please let me know if you would like to work with us, I am particularly looking for motivated students, talented postdoctoral fellows, research collaborators and commercial partners.
Tetraspanin 6: a pivotal protein of the multiple vesicular body determining exosome release and lysosomal degradation of amyloid precursor protein fragments.
Guix FX, Sannerud R, Berditchevski F, Arranz AM, Horré K, Snellinx A, Thathiah A, Saido T, Saito T, Rajesh S, Overduin M, Kumar-Singh S, Radaelli E, Corthout N, Colombelli J, Tosi S, Munck S, Salas IH, Annaert W, De Strooper B.
Mol Neurodegener. (2017) Mar 10;12(1):25.
The CD63-Syntenin-1Complex Controls Post-Endocytic Trafficking of Oncogenic Human Papillomaviruses.
Gräßel L, Fast LA, Scheffer KD, Boukhallouk F, Spoden GA, Tenzer S, Boller K, Bago R, Rajesh S, Overduin M, Berditchevski F, Florin L.
Sci Rep. 2016 Aug 31;6:32337.
A method for detergent-free isolation of membrane proteins in their local lipid environment.
Lee SC, Knowles TJ, Postis VL, Jamshad M, Parslow RA, Lin YP, Goldman A, Sridhar P, Overduin M, Muench SP, Dafforn TR.
Nat Protoc. (2016) Jul;11(7): 1149-62.
Structural Mechanisms and Drug Discovery Prospects of Rho GTPases.
Smithers CC, Overduin M.
Cells. (2016)Jun 13; 5(2).
NMR of Membrane Proteins: Beyond Crystals.
Rajesh S, Overduin M,
Bonev BB. Adv Exp Med Biol. (2016) 922: 29-42.
Mechanism of intermediate filament recognition by plakin repeat domains revealed by envoplakin targeting of vimentin.
Fogl C, Mohammed F, Al-Jassar C, Jeeves M, Knowles TJ, Rodriguez-Zamora P, White SA, Odintsova E, Overduin M, Chidgey M.
Nat Commun. (2016) Mar 3;7: 10827.
Characterization of a Putative Receptor Binding Surface on Skint-1, a Critical Determinant of Dendritic Epidermal T Cell Selection.
Salim M, Knowles TJ, Hart R, Mohammed F, Woodward MJ, Willcox CR, Overduin M, Hayday AC, Willcox BE.
J Biol Chem. (2016) Apr 22;291(17): 9310-21.
Membrane and Protein Interactions of the Pleckstrin Homology Domain Superfamily.
Lenoir M, Kufareva I, Abagyan R, Overduin M.
Membranes (Basel). (2015) Oct 23;5(4): 646-63.
Small-Molecule Protein-Protein Interaction Inhibitor of Oncogenic Rho Signaling.
Diviani D, Raimondi F, Del Vescovo CD, Dreyer E, Reggi E, Osman H, Ruggieri L, Gonano C, Cavin S, Box CL, Lenoir M, Overduin M, Bellucci L, Seeber M, Fanelli F.
Cell Chem Biol. (2016) Sep 22;23(9):1135-46.
Cross-species chimeras reveal BamA POTRA and β-barrel domains must be fine-tuned for efficient OMP insertion.
Browning DF, Bavro VN, Mason J, Sevastsyanovich YR, Rossiter AE, Jeeves M, Wells TJ, Knowles T, Cunningham AF, Donald J, Palmer T, Overduin M,
Henderson IR Mol Micro, (2015) 97(4): 646-59.
Structural basis of dynamic membrane recognition by trans-Golgi network specific FAPP proteins.
Lenoir M, Grzybek M, Majkowski M, Rajesh S, Kaur J, Coskun Ü, Overduin M.
J Mol Biol. (2015) 427(4):966-81.
Structure-based Drug Design using NMR
Jeeves M, Quill L, Overduin M.
eMagRes (2015) 4, 231–240.
Discovery of novel membrane binding structures and functions.
Kufareva I, M Lenoir, Dancea F, Sridhar P, Rausch E, Bissig C, Gruenberg J, Abagyan R, Overduin M.
Biochem Cell Biol, (2014) 92(6): 555-563.
Ambidextrous Binding of Membrane Bilayers by a Soluble Metalloproteinase.
Koppisetti RK, Fulcher YG, Jurkevic A, Prior SH, Xu J, Lenoir M, Overduin M, Van DorenSR.
Nature Comms. (2014) 5: 5552.
Structural Insights into the Activation of the RhoA GTPase by the Lbc Oncoprotein.
Lenoir, M, Sugawara M, Kaur J, Ball LJ, Overduin M
J Biol Chem (2014) 289(34): 23992-4004.
Targeting Protein Tyrosine Phosphatase SHP2 for therapeutic intervention in cancer.
Butterworth S, Overduin M and Barr AJ.
Future Med Chem (2014) 6(12):1423-37.
Mechanistic basis of desmosome-targeted diseases.
Al-Jassar C, Bikker H, Overduin M, Chidgey M.
J Mol Biol. (2013) 425(21): 4006-22.
Hinged plakin domains provide specialized degrees of articulation in envoplakin, periplakin and desmoplakin.
Al-Jassar C, Bernado P, Chidgey M, Overduin M.
PLoS ONE (2013) 8(7): e69767.
Viral infection controlled by calcium dependent recognition of late endosome-specific lipid by the Alix Bro1 domain.
Bissig C, Lenoir M, Velluz MC, Kufarena I, Abagyan R, Overduin M, Gruenberg.
J Dev Cell (2013) 25: 364-73.
PtdIns(4)P signalling and recognition sytems.
Lenoir M, Overduin M.
Adv Exp Med Biol (2013) 991: 59-83.
Structural basis of ligand interactions of the large extracellular domain of tetraspanin CD81.
Rajesh S, Sridhar P, Tews BA, Fénéant L, Cocquerel L, Ward DG, Berditchevski F, Overduin M.
J Virol (2012) 86(18): 9606-16.
Production of membrane proteins without cells or detergents.
Rajesh S, Knowles TJ, Overduin M.
New Biotechnology (2011) 28(3): 250-4.
Structure and function of BamE within the outer membrane and the β-barrel assembly machine.
Knowles TJ, Browning DF, Jeeves M, Maderbocus R, Rajesh S, Sridhar P, Manoli E, Emery D, Sommer U, Spencer A, Leyton DL, Squire D, Chaudhuri RR, Viant MR, Cunningham AF, Henderson IR, Overduin M.
EMBO Reports (2011) 12(2): 123-8.
Binding to syntenin-1 defines a new mode of ubiquitin-based interactions regulated by phosphorylation.
Rajesh S, Bago R, Odintsova E, Muratov G, Sridhar P, Rajesh S, Overduin M, Berditchevski F.
J Biol Chem. (2011) 286(45):39606-14.
The nonlinear structure of the desmoplakin plakin domain and the effects of cardiomyopathy-linked mutations.
Al-Jassar C, Knowles T, Jeeves M, Kami K, Bikker H, Overduin M, Chidgey M.
J Mol Biol. (2011) 411(5): 1049-61.
Structural Basis of Wedging the Golgi Membrane by FAPP Pleckstrin Homology Domains.
Lenoir M, Coskun U, Grzybek M, Cao X, Buschhorn SB, James J, Simons K, Overduin M.
EMBO Reports (2010) 11(4):279-84.