Seminar: Dragomir Milovanovic, theme Cancer development and immune defence

Length matters: Hydrophobic mismatch regulates trafficking and lateral segregation of SNARE proteins

Date:
4 December 2015 12:00 hrs. - 13:00 hrs.
Location:
Figdor Lecture Theatre, 8th floor RIMLS Building, Geert Grooteplein 26-28, route 289
Title:
Length matters: Hydrophobic mismatch regulates trafficking and lateral segregation of SNARE proteins
Speaker(s):

Dragomir Milovanovic, Departments of Neurobiology, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany

Host(s):

Geert van den Bogaart, Dept. of Tumor Immunology, RIMLS

04-12-2015 12:00:0004-12-2015 13:00:00Europe/AmsterdamLength matters: Hydrophobic mismatch regulates trafficking and lateral segregation of SNARE proteins Figdor Lecture Theatre, 8th floor RIMLS Building, Geert Grooteplein 26-28, route 289Rimlsrimls@radboudumc.nl

Remarks / more information:

undefinedundefinedThe clustering of proteins and lipids in distinct microdomains is emerging as an important principle for the spatial patterning of biological membranes (1). In this seminar, I will present a truly multidisciplinary approach to tackle membrane patterning that includes biochemical assays (in vitro membrane reconstitutions, analysis of cell membranes), cutting-edge biophysical analysis (two-color-STED nanoscopy, FCS, FRET, imaging ellipsometry) and molecular dynamics simulations.

Using plasma membrane-resident SNARE proteins as model, we now show that cholesterol-induced hydrophobic mismatch between the transmembrane domains and the membrane lipids not only suffices to induce clustering of proteins, but can also lead to the segregation of structurally closely homologous membrane proteins in distinct membrane domains (2). Domain formation is further fine-tuned by interactions with polyanionic phosphoinositides and proteins. Interestingly, Ca2+ acts as a charge bridge that connects multiple syntaxin 1/PI(4,5)P2 clusters into larger domains (3). Beyond lateral segregation, our most recent data in model membranes indicate that hydrophobic differences in the transmembrane domain length may contribute to trafficking of VAMP3 and VAMP8 SNAREs into distinct organelles.

Segregating SNARE proteins into distinct clusters at the plasma membrane has three key functional implications: (i) clusters act as the local hot spots for the vesicle recruitment (4), (ii) the local enrichment provides sufficient number of proteins necessary for the fast, evoked synaptic release(5), (iii) closely homologous SNARE proteins such as synataxin 1 and 4 are segregated in non-overlapping membrane domains which is essential for their distinct roles in regulated (sytnaxin 1) and constitutive (syntaxin 4) exocytosis(2). Overall, our findings demonstrate that the structural organization of membranes is governed by a hierarchy of interactions with hydrophobic mismatch emerging as one of the fundamental physical principles.

Publications: 

  1. Organization and dynamics of SNARE proteins in the presynaptic membrane. Frontiers in Physiology, 6:89, 2015
  2.  Hydrophobic mismatch sorts SNARE proteins into distinct membrane domains. Nature Communications, 6: 5984, 2015 
  3.  Milovanovic D, Platen M, Junius M, Diederichsen U, Schaap I, Honigmann A, Hell SW, Jahn R, van den Bogaart G. manuscript in preparation.
  4. Phosphatidylinositol 4,5-bisphosphate clusters act as molecular beacons for vesicle recruitment. Nature Structural & Molecular Biology, 20: 679–86, 2013
  5. Resolving single membrane fusion events on planar pore-spanning membranes. Scientific Reports, 5: 12006, 2015


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