Dynamin is a GTPase that regulates late events in clathrin‐coated vesicle formation. Our current working model suggests that dynamin is targeted to coated pits in its unoccupied or GDP‐bound form, where it is initially distributed uniformly throughout the clathrin lattice. GTP/GDP exchange triggers its release from these sites and its assembly into short helices that encircle the necks of invaginated coated pits like a collar. GTP hydrolysis, which is required for vesicle detachment, presumably induces a concerted conformation change, (...) tightening the collar. Unlike most of its GTPase cousins that serve as molecular switches, dynamin has a low affinity for GTP, a very high intrinsic rate of GTP hydrolysis and functions as a homo‐oligomer. A concerted conformational change resulting from coordinated GTP hydrolysis by the dynamin oligomer might be sufficient to generate force. In this case, dynamin would be the first GTPase identified that acts as a structural protein with mechano‐chemical function. (shrink)

Recently, Gao et al. and Chappie et al. elucidated the crystal structures of the polytetrameric stalk domain of the dynamin‐like virus resistance protein, MxA, and of the G‐domain dimer of the large, membrane‐deforming GTPase, dynamin, respectively. Combined, they provide a hypothetical oligomeric structure for the complete dynamin protein. Here, it is discussed how the oligomers are expected to form and how they participate in dynamin mediated vesicle fission during the process of endocytosis. The proposed oligomeric structure (...) is compared with the novel mechanochemical model of dynamin function recently proposed by Bashkirov et al. and Pucadyil and Schmid. In conclusion, the new model of the dynamin oligomer has the potential to explain how short self‐limiting fissogenic dynamin assemblies are formed and how concerted GTP hydrolysis is achieved. The oligomerisation of two other dynamin superfamily proteins, the guanylate binding proteins (GBPs) and the immunity‐related GTPases (IRGs), is addressed briefly. (shrink)

Graphical AbstractWhereas clathrin-mediated endocytosis (CME) exists in all eukaryotic cells, we first detect classical dynamin in Ichthyosporid, a single-cell, metazoan precursor. Based on a key functional residue in its pleckstrin homology domain, we speculate that the evolution of metazoan dynamin coincided with the specialized need for regulated CME during neurotransmission.

Fission of cellular membranes is ubiquitous and essential for life. Complex protein machineries, such as the dynamin and ESCRT spirals, have evolved to mediate membrane fission during diverse cellular processes, for example, vesicle budding. A new study suggests that non-specialized membrane-bound proteins can induce membrane fission through mass action due to protein crowding. Because up to 2/3 of the mass of cellular membranes is contributed by proteins, membrane protein crowding is an important physiological parameter. Considering the complexity of membrane (...) shape transitions during a fission reaction, spatial and temporal variability in protein distribution, and the abundance of intrinsically disordered regions in proteins on an invaginating membrane, protein crowding can have diverse consequences for fission in the cell. The question is, how and to what extent this mechanism combines with the action of dedicated fission machineries. Membrane fission, which is required for formation of vesicles or cytokinesis, can be carried out by specialized proteins like dynamin and the ESCRT complex. Recent work suggests that fission of cellular membranes, which are densely packed with proteins, can also be induced by protein crowding due to high entropic tension. (shrink)

"Audaces fortuna invat. Dynamin sophian kyle baraka. Many or few, always bold"--Front cover.

Comment la notion aristotelicienne de puissance s'est-elle constituee? Comment Aristote peut-il designer du meme nom de dynamis a la fois le principe du changement et l'etre en puissance en tant qu'il est distingue de l'etre en acte? L'histoire de la dynamis correspond-elle a l'effacement d'un sens primitivement intensif, qui serait celui de la force, au profit du sens aristotelicien de potentialite? Plutot que d'aborder ces questions dans les limites d'une lecture interne du Livre Theta de la Metaphysique sur la puissance (...) et l'acte, ou meme du corpus aristotelicien, la presente recherche plonge d'abord la notion de puissance dans son histoire pre-aristotelicienne, philosophique et non-philosophique. Si les termes d'energeia et d'entelekheia, par lesquels Aristote designe ce qui est en acte, sont des neologismes qui possedent la precision du vocabulaire technique, le mot dynamis appartient au grec courant et comporte une polysemie qui complique la comprehension de son usage. Ce livre veut articuler les sens philosophiques de cette notion chez Aristote a partir de son histoire depuis Homere et Hesiode, a travers Democrite, Xenophon ou encore le corpus hippocratique. Mais l'etude des principaux textes (poetiques, politiques, medicaux, mathematiques, philosophiques) est conduite selon un fil conducteur precis, dicte par l'emploi dominant de ce terme dans la clause restrictive kata dynamin (autant que je le peux). Les significations et l'histoire de la dynamis sont reevaluees a partir de ce nouveau point de depart. L'heritage platonicien est aussi pris en compte pour degager finalement le sens de la critique aristotelicienne de la puissance, qui met en lumiere son indetermination axiologique et ontologique, sans renoncer aux sens de capacite et de force. Nous ne cherchons pas a proposer une etude lexicographique, mais a situer la pensee aristotelicienne de la puissance et de l'acte dans une histoire conceptuelle, en esperant qu'elle gagnera ainsi en coherence et en clarte. (shrink)

Aristoteles unterscheidet zwischen zwei Arten, das Wort „dynaton" zu gebrauchen. Die erste dieser beiden Verwendungsweisen dient zur Zuschreibung von Vermögen (dynaton kata dynamin), die zweite entspricht unserer Verwendung des logisch-alethischen Modaloperators „Es ist möglich, dass" (dynaton ou kata dynamin). Ich argumentiere dafür, dass wichtige Unterschiede zwischen Vermögensprädikationen und Modalaussagen bestehen. Ich nenne mehrere Gründe dafür, dass Vermögensprädikationen keine Modalaussagen sind, zeige aber auch, dass Vermögensprädikationen zwei modale Elemente haben: Sie implizieren erstens nichttriviale Modalaussagen, weil es keine Vermögen für (...) Unmögliches gibt. Und sie implizieren zweitens nichttriviale Aussagen über kontrafaktische Situationen, weil sie Aussagen über kausale Rollen sind. (shrink)

Two key questions in the autophagy field are the mechanisms that underlie the signals for autophagy initiation and the source of membrane for expansion of the nascent membrane, the phagophore. In this review, we discuss recent findings highlighting the role of the classical endosomal pathway, from plasma membrane to lysosome, in the formation and expansion of the phagophore and subsequent degradation of the autophagosome contents. We also highlight the striking conservation of regulatory factors between the two pathways, including those regulating (...) membrane budding and fusion, and the role of the lysosome in sensing the nutrient status of the cell, regulating mTORC1 activity, and ultimately the initiation of autophagy.Editor's suggested further reading in BioEssays The evolution of dynamin to regulate clathrin‐mediated endocytosis Abstract. (shrink)

We propose a signaling pathway in which cell‐extracellular matrix (ECM) adhesion components PINCH‐1 and kindlin‐2 sense mechanical signals from ECM and link them to proline biosynthesis, a vital metabolic pathway for macromolecule synthesis, redox balance, and ECM remodeling. ECM stiffening promotes PINCH‐1 expression via integrin signaling, which suppresses dynamin‐related protein 1 (DRP1) expression and mitochondrial fission, resulting in increased kindlin‐2 translocation into mitochondria and interaction with Δ1‐pyrroline‐5‐carboxylate (P5C) reductase 1 (PYCR1). Kindlin‐2 interaction with PYCR1 protects the latter from proteolytic (...) degradation, leading to elevated PYCR1 level. Additionally, PINCH‐1 promotes P5C synthase (P5CS) expression and P5C synthesis, which, together with increased PYCR1 level, support augmented proline biosynthesis. This signaling pathway is frequently activated in fibrosis and cancer, resulting in increased proline biosynthesis and excessive collagen matrix production, which in turn further promotes ECM stiffening. Targeting this signaling pathway, therefore, may provide an effective strategy for alleviating fibrosis and cancer progression. (shrink)

Clathrin‐mediated endocytosis is a major route for the retrieval of plasma‐membrane cargoes, and defects of this process can cause catastrophic human dysfunctions. However, the processes governing how a clathrin‐coated profile (ccp) is initiated are still murky. Despite an ever‐growing cast of molecules proposed as triggers of ccp nucleation and increasingly sophisticated bioimaging techniques examining clathrin‐mediated endocytosis, it is yet unknown if ccp formation is governed by a universal mechanism. A recent paper by Cocucci et al. has tracked single‐molecule events to (...) identify that stable accumulation of ccps requires the near‐simultaneous arrival of two AP2 adaptors bridged by one clathrin triskelion. This commentary examines the role of AP2 in cargo‐mediated endocytosis in the light of recent advances in biophotonics, chemical inhibitors and genetics, examines the claims of other molecules to be the initiators of ccp formation and proposes future directions in research into this topic.Editor's suggested further reading in BioEssays: The evolution of dynamin to regulate clathrin‐mediated endocytosis AbstractClathrin‐mediated endocytosis: What works for small, also works for big Abstract. (shrink)