University of Pittsburgh Department of Cell Biology
  • Research

    Our laboratory is interested in the fundamental question of how the cell controls the morphology and structure of its membranes. To this end, we are particularly interested in understanding endosomal sorting and the molecular mechanisms of endosomal membrane remodeling. Remodeling is performed by members of several protein families, including the SNX-BAR proteins and the dynamin-related proteins (DRPs). SNX-BAR and DRP mutations are both associated with health challenges, including neurodegenerative diseases such as Alzheimer’s and Parkinson’s.

    We use structural and biophysical approaches, supplemented with in vivo and high throughput genetic studies in the model organism S. cerevisiae. Recently, we used cryo-electron microscopy and X-ray crystallography, combined with live cell imaging and functional cell biological approaches, to characterize a retromer-dependent SNX-BAR involved in retrograde trafficking from the endosome as well as a DRP involved in endosomal membrane remodeling. In both cases, the structures we generated provided novel insights into the regulation of their function by self-assembly.

    Our current work aims to understand how various SNX-BAR complexes are regulated and how they engage with their respective cargoes and binding partners, including members of the DRP family.

  • Publications

    1. Ford MGJ, Chappie JS. The structural biology of the dynamin-related proteins: New insights into a diverse, multitalented family.. Traffic. 2019 Jul 12;():. doi: 10.1111/tra.12676. PubMed PMID: 31298797;
    2. Varlakhanova NV, Tornabene BA, Ford MGJ. Ivy1 is a negative regulator of Gtr-dependent TORC1 activation.. J Cell Sci. 2018 Sep 7;131(17):. pii: jcs218305. doi: 10.1242/jcs.218305. PubMed PMID: 30097557;
    3. Varlakhanova NV, Alvarez FJD, Brady TM, Tornabene BA, Hosford CJ, Chappie JS, Zhang P, Ford MGJ. Structures of the fungal dynamin-related protein Vps1 reveal a unique, open helical architecture.. J Cell Biol. 2018 Oct 1;217(10):3608-3624. doi: 10.1083/jcb.201712021. PubMed PMID: 30087125;
    4. Varlakhanova NV, Mihalevic MJ, Bernstein KA, Ford MGJ. Pib2 and the EGO complex are both required for activation of TORC1.. J Cell Sci. 2017 Nov 15;130(22):3878-3890. doi: 10.1242/jcs.207910. PubMed PMID: 28993463;
    5. Ford MG, Jenni S, Nunnari J. The crystal structure of dynamin. Nature. 2011 Sep 18;477(7366):561-6. doi: 10.1038/nature10441. [link]
    6. Olesen LE, Ford MG, Schmid EM, Vallis Y, Babu MM, Li PH, Mills IG, McMahon HT, Praefcke GJ. Solitary and repetitive binding motifs for the AP2 complex alpha-appendage in amphiphysin and other accessory proteins. J Biol Chem. 2008 Feb 22;283(8):5099-109. Epub 2007 Nov 6. [link]
    7. Schmid EM, Ford MG, Burtey A, Praefcke GJ, Peak-Chew SY, Mills IG, Benmerah A, McMahon HT. Role of the AP2 beta-appendage hub in recruiting partners for clathrin-coated vesicle assembly. PLoS Biol. 2006 Sep;4(9):e262. [link]
    8. Praefcke GJ, Ford MG, Schmid EM, Olesen LE, Gallop JL, Peak-Chew SY, Vallis Y, Babu MM, Mills IG, McMahon HT. Evolving nature of the AP2 alpha-appendage hub during clathrin-coated vesicle endocytosis. EMBO J. 2004 Nov 10;23(22):4371-83. Epub 2004 Oct 21. [link]
    9. Ford MG, Mills IG, Peter BJ, Vallis Y, Praefcke GJ, Evans PR, McMahon HT. Curvature of clathrin-coated pits driven by epsin. Nature. 2002 Sep 26;419(6905):361-6. [link]
    10. Ford MG, Pearse BM, Higgins MK, Vallis Y, Owen DJ, Gibson A, Hopkins CR, Evans PR, McMahon HT. Simultaneous binding of PtdIns(4,5)P2 and clathrin by AP180 in the nucleation of clathrin lattices on membranes. Science. 2001 Feb 9;291(5506):1051-5. [link]

     

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