Research:

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:

1. Extending from the genetic code to a more complete biological code that includes not nucleic acid and protein information but also membrane codes. We have discovered memteins (membrane protein assemblies), regulatory MET-stops and PIP-stops, and the elusive lipidons that dictate membrane reader functions. We are also determining how proteins recognize lipids and reshape membranes. Progress includes 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. Along the way we co-developed predictive "MODA" software for identifying novel membrane binding surfaces on virtually any protein structure and SMALP system for making native nanodiscs. Ultimately we hope to decipher the entirety of the lipid code whereby proteins recognize complex membrane surfaces, shape dynamic organelle structures and initiate localized signaling.
   
   
2. Disease mechanisms of oncogenic proteins, prions, and systems used by viral and bacterial pathogens with an emphasis on those that occur on membranes, as well as effects of critical mutations and modifications. Our targets include the Fgd5 GTPase, CaMK1D kinase, Shp2 phosphatase, tetraspanins including the CD81 receptor for Hepatitis C virus, and desmosomal proteins that mediate cell adhesion and cytoskeletal attachment. We elucidate the structures, dynamics and interactions of these systems, and identify new sites and ligands that can inform the design of novel therapeutic agents.
   
   
3. 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 biolayer interferometry, microscale diffusion, isothermal titration calorimetry and nuclear magnetic resonance spectroscopy are being harnessed to identify ligands and binding modes. Polymers are being used to solubilize and study challenging membrane protein targets with styrene maleic acid lipid particles (SMALPs). These tools are shared open access facilities including Molscreen and NANUC, and through consortia including the SMALP Network.
   
   

   Our lab's ethos is team-based and collaborative, and involves international teams 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 startups to develop new products, and engage with leaders to inform policy and spur innovation.

 

Selected Publications:

The phosphoinositide code is read by a plethora of protein domains.
Overduin M, Kervin TA.
Expert Rev Proteomics. 2021 Aug 23:1-20. doi: 10.1080/14789450.2021.1962302. Online ahead of print.

Tetraspanin 6 (Tspan6) is a new regulator of carcinogenesis in colorectal cancer
Andrijes R, Hejmadi RK, Pugh M, Rajesh S, Novitskaya V, Noyvert B, Ibrahim M, Overduin M, Tselepis C, Middleton G, Győrffy B, Beggs A D, Berditchevski F.
PNAS USA, in press.

Phosphoinositide Recognition Sites Are Blocked by Metabolite Attachment.
Kervin TA, Wiseman BC, Overduin M.
Front Cell Dev Biol. 2021 Jul 22;9:690461. doi: 10.3389/fcell.2021.690461.

Structures and Dynamics of Native-State Transmembrane Protein Targets and Bound Lipids.
Overduin M, Trieber C, Prosser RS, Picard LP, Sheff JG.
Membranes (Basel). 2021 Jun 17;11(6):451. doi: 10.3390/membranes11060451. Review.

Regulation of the Phosphoinositide Code by Phosphorylation of Membrane Readers.
Kervin TA, Overduin M.
Cells. 2021 May 14;10(5):1205. doi: 10.3390/cells10051205.

Structural biology of endogenous membrane protein assemblies in native nanodiscs.
Brown CJ, Trieber C, Overduin M.
Curr Opin Struct Biol. 2021 Apr 26;69:70-77. doi: 10.1016/j.sbi.2021.03.008. Online ahead of print.

Multisite interactions of prions with membranes and native nanodiscs.
Overduin M, Wille H, Westaway D.
Chem Phys Lipids. 2021 May;236:105063. doi: 10.1016/j.chemphyslip.2021.105063. Epub 2021 Feb 15.

Fgd5 is a Rac1-specific Rho GEF that is selectively inhibited by aurintricarboxylic acid.
Park S, Guo Y, Negre J, Preto J, Smithers CC, Azad AK, Overduin M, Murray AG, Eitzen G.
Small GTPases. 2021 Mar;12(2):147-160. doi: 10.1080/21541248.2019.1674765. Epub 2019 Oct 10.

Structure-function analyses of dual-BON domain protein DolP identifies phospholipid binding as a new mechanism for protein localisation to the cell division site
Bryant JA, Morris FC, Knowles TJ, Maderbocus R, Heinz E, Boelter G, Alodaini D, Colyer A, Wotherspoon P, Staunton KA, Jeeves M, Browning DF, Sevastsyanovich YR, Wells TJ, Rossiter AE, Bavro VN, Sridhar P, Ward DG, Mamou G, Chong ZS, Rahul S, Teo A, Kleanthous C, Chng SS, Roper DI, Lithgow T, Cunningham AF, Banzhaf M, Overduin M, Henderson IR.
eLife, 9:e62614.

Native nanodiscs formed by styrene maleic acid copolymer derivatives help recover infectious prion multimers bound to brain-derived lipids.
Esmaili M, Tancowny BP, Wang X, Moses A, Cortez LM, Sim VL, Wille H, Overduin M.
J Biol Chem. 2020 Jun 19;295(25):8460-8469. doi: 10.1074/jbc.RA119.012348. Epub 2020 May 1.

Molecular mechanism of intermediate filament recognition by plakin proteins.
Mohammed F, Trieber C, Overduin M, Chidgey M.
Biochim Biophys Acta Mol Cell Res. 2020 Nov;1867(11):118801. doi: 10.1016/j.bbamcr.2020.118801. Epub 2020 Jul 23.

Homogeneous nanodiscs of native membranes formed by stilbene-maleic-acid copolymers.
Esmaili M, Brown CJ, Shaykhutdinov R, Acevedo-Morantes C, Wang YL, Wille H, Gandour RD, Turner SR, Overduin M.
Nanoscale. 2020 Aug 20;12(32):16705-16709. doi: 10.1039/d0nr03435e.

The effect of hydrophobic alkyl sidechains on size and solution behaviors of nanodiscs formed by alternating styrene maleamic copolymer.
Esmaili M, Acevedo-Morantes C, Wille H, Overduin M.
Biochim Biophys Acta Biomembr. 2020 Oct 1;1862(10):183360. doi: 10.1016/j.bbamem.2020.183360. Epub 2020 May 23.

Discovery of Highly Selective Inhibitors of Calmodulin-Dependent Kinases That Restore Insulin Sensitivity in the Diet-Induced Obesity in Vivo Mouse Model.
Fromont C, Atzori A, Kaur D, Hashmi L, Greco G, Cabanillas A, Nguyen HV, Jones DH, Garzón M, Varela A, Stevenson B, Iacobini GP, Lenoir M, Rajesh S, Box C, Kumar J, Grant P, Novitskaya V, Morgan J, Sorrell FJ, Redondo C, Kramer A, Harris CJ, Leighton B, Vickers SP, Cheetham SC, Kenyon C, Grabowska AM, Overduin M, Berditchevski F, Weston CJ, Knapp S, Fischer PM, Butterworth S.
J Med Chem. 2020 Jul 9;63(13):6784-6801. doi: 10.1021/acs.jmedchem.9b01803. Epub 2020 Jun 22.

Vimentin binding of the periplakin linker requires basic linker domain residues D176 and E187.
Odintsova E, F Mohammed, C Trieber, P Rodriguez-Zamora, C Al-Jassar, Tzu-Han Huang, C Fogl, T Knowles, P Sridhar, J Kumar, M Jeeves, M Chidgey, M Overduin.
Communs Bio 3: 83.

The ER chaperone calnexin controls mitochondrial positioning and respiration.
Gutiérrez T, Qi H, Yap MC, Tahbaz N, Milburn LA, Lucchinetti E, Lou PH, Zaugg M, LaPointe PG, Mercier P, Overduin M, Bischof H, Burgstaller S, Malli R, Ballanyi K, Shuai J, Simmen T.
Sci Signal. 2020 Jun 30;13(638):eaax6660. doi: 10.1126/scisignal.aax6660.

Defining Fgd5 as a Rac1-specific Rho GEF and identification of inhibitors by SPR based compound screening.
Park S, Guo Y, Preto J, Smithers CC, Azad AK, Overduin M, Murray A, Eitzen G. 2019.
Small GTPases 10: 1-14.

Native nanodiscs and the convergance of lipidomics, metabolomics, interactomics and proteomics.
Overduin M, Esmaili M.
Appl Sci, 9(6), 1230.

Memtein: The fundamental unit of membrane-protein structure and function.
Overduin M, Esmaili M.
Chem Phys Lipids. 2019 Jan;218:73-84. doi: 10.1016/j.chemphyslip.2018.11.008. Epub 2018 Nov 30.

Structure and function of the Fgd family of divergent FYVE domain proteins 1.
Eitzen G, Smithers CC, Murray AG, Overduin M.
Biochem Cell Biol. 2019 Jun;97(3):257-264. doi: 10.1139/bcb-2018-0185. Epub 2018 Oct 11. Review.

Uncoupling ITIM receptor G6b-B from tyrosine phosphatases Shp1 and Shp2 disrupts murine platelet homeostasis.
Geer MJ, van Geffen JP, Gopalasingam P, Vögtle T, Smith CW, Heising S, Kuijpers MJE, Tullemans BME, Jarvis GE, Eble JA, Jeeves M, Overduin M, Heemskerk JWM, Mazharian A, Senis YA.
Blood. 2018 Sep 27;132(13):1413-1425. doi: 10.1182/blood-2017-10-802975. Epub 2018 Jun 11.

Phosphorylation of conserved phosphoinositide binding pocket regulates sorting nexin membrane targeting.
Lenoir M, Ustunel C, Rajesh S, Kaur J, Moreau D, Gruenberg J, Overduin M.
Nat Commun. 2018 Mar 8;9(1):993. doi: 10.1038/s41467-018-03370-1.