Identification and function of conformational dynamics in the multidomain GTPase dynamin

The EMBO Journal
Saipraveen SrinivasanSandra L Schmid

Abstract

Vesicle release upon endocytosis requires membrane fission, catalyzed by the large GTPase dynamin. Dynamin contains five domains that together orchestrate its mechanochemical activity. Hydrogen-deuterium exchange coupled with mass spectrometry revealed global nucleotide- and membrane-binding-dependent conformational changes, as well as the existence of an allosteric relay element in the α2(S) helix of the dynamin stalk domain. As predicted from structural studies, FRET analyses detect large movements of the pleckstrin homology domain (PHD) from a 'closed' conformation docked near the stalk to an 'open' conformation able to interact with membranes. We engineered dynamin constructs locked in either the closed or open state by chemical cross-linking or deletion mutagenesis and showed that PHD movements function as a conformational switch to regulate dynamin self-assembly, membrane binding, and fission. This PHD conformational switch is impaired by a centronuclear myopathy-causing disease mutation, S619L, highlighting the physiological significance of its role in regulating dynamin function. Together, these data provide new insight into coordinated conformational changes that regulate dynamin function and couple membrane binding, o...Continue Reading

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Citations

May 27, 2017·Nature Communications·Yang ChenSong Gao
Jan 24, 2018·Journal of Cell Science·Begoña Ugarte-UribeAna J García-Sáez
Apr 18, 2018·Annual Review of Biochemistry·Marcel MettlenSandra L Schmid
Aug 1, 2019·Molecular Biology of the Cell·Raghav Kalia, Adam Frost
Aug 5, 2017·Expert Opinion on Drug Discovery·Glenn R MassonJohn E Burke
Jun 11, 2020·Mass Spectrometry Reviews·Ming Huang, Yinsheng Wang
Jun 25, 2020·Molecular Biology of the Cell·Madhura BhaveSandra L Schmid
Nov 15, 2018·Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics·Mo ZhaoJames J Dowling
Sep 8, 2017·Scientific Reports·Christopher A FrancyJason A Mears
May 13, 2021·Molecular Biology of the Cell·Krishnakanth BaratamAnand Srivastava
Jul 14, 2021·Nature Cell Biology·Xiaodong ChengNing Fang
Nov 9, 2021·Frontiers in Cellular Neuroscience·Tara C TassinJoseph P Albanesi

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