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Curr Biol. 1999 Mar 11;9(5):261-4.

Dominant-negative inhibition of receptor-mediated endocytosis by a dynamin-1 mutant with a defective pleckstrin homology domain.

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Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.


The dynamins are 100 kDa GTPases involved in the scission of endocytic vesicles from the plasma membrane [1]. Dynamin-1 is present in solution as a tetramer [2], and undergoes further self-assembly following its recruitment to coated pits to form higher-order oligomers that resemble 'collars' around the necks of nascent coated buds [1] [3]. GTP hydrolysis by dynamin in these collars is thought to accompany the 'pinching off' of endocytic vesicles [1] [4]. Dynamin contains a pleckstrin homology (PH) domain that binds phosphoinositides [5] [6], which in turn enhance both the GTPase activity [5] [7] [8] and self-assembly [9] [10] of dynamin. We recently showed that the dynamin PH domain binds phosphoinositides only when it is oligomeric [6]. Here, we demonstrate that interactions between the dynamin PH domain and phosphoinositides are important for dynamin function in vivo. Full-length dynamin-1 containing mutations that abolish phosphoinositide binding by its PH domain was a dominant-negative inhibitor of receptor-mediated endocytosis. Mutated dynamin-1 with both a defective PH domain and impaired GTP binding and hydrolysis also inhibited receptor-mediated endocytosis. These findings suggest that the role of the PH domain in dynamin function differs from that seen for other PH domains. We propose that high-avidity binding to phosphoinositide-rich regions of the membrane by the multiple PH domains in a dynamin oligomer is critical for dynamin's ability to complete vesicle budding.

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