Dynamin

Dynamin is the founding member of the dynamin superfamily. The multi-domain protein oligomerizes around the neck of clathrin-coated vesicles and induces vesicle scission in a GTP hydrolysis-dependent fashion. This membrane trafficking pathway mediates 50% of all uptake processes from the plasma membrane. The molecular mechanisms governing vesicle scission are, however, poorly understood.

Based on our previous work on the MxA stalk, we determined the X-ray structure of nearly full-length dynamin in the absence of nucleotides. Dynamin shows a four-domain architecture composed of the GTPase domain, the bundle signalling element (BSE), the stalk and the lipid binding pleckstrin homology (PH) domain. Interestingly, an interaction site between the stalk and the PH domain is often mutated in patients suffering from Charcot-Marie-Tooth neuropathy or centronuclear myopathy, two congenital diseases leading to progressive muscle weakness of the limbs. Dynamin was oligomerizing in the crystals via the stalks which assembled in a criss-cross fashion. Interestingly, the BSE of each monomer contacts the stalk of the neighbouring monomer, and this interaction appeared to control the activity of dynamin. Supported by biochemical and cell-based functional assays, we proposed a molecular model for helical dynamin oligomers. Furthermore, we suggested how the interplay between the dynamin domains contributes to the mechano-chemical coupling in the dynamin family. Finally, we introduced a dynamic model how GTP binding and hydrolysis induces scission of the vesicle neck.

 

Publications

Faelber K., Posor Y., Gao S., Held M., Roske Y., Schulze D., Haucke V., Noé F., Daumke O. (2011) Crystal structure of nucleotide-free dynamin. Nature 477, 556-60.

 

Faelber K., Held M., Gao S., Posor Y., Haucke V., Noé F., and Daumke O. (2012). Structural insights into dynamin-mediated membrane fission. Structure 20, 1621-28 (Review).

 

Researchers in my group

Katja Fälber (PostDoc)

 

Collaborators

Frank Noé, Freie Universität, Volker Haucke (Leibniz-Institut für Molekulare Pharmakologie).

 

 

 

Figure 1: Domain architecture of dynamin (a) and crystal structure of the dynamin dimer (b).


Figure 2: Model of action for the dynamin oligomer at the neck of clathrin-coated vesicles. (1) Dynamin oligomerizes around the neck of a clathrin-coated vesicle (here depicted as a membrane tubule). (2) When the oligomer has surrounded the bud neck once, GTPase domains of neighbouring filaments dimerize and induce the GTPase reaction. (3) The resulting conformational changes in the BSEs pull neighbouring filaments along each other, leading to constriction of the oligomer and the bud neck. (4) In the GDP-bound form, GTPase domains dissociate. We suggested that either during step 3 or 4, the membrane is cleaved.