Cell Science at a Glance 3427

Dynamins at a glance characteristic domains. are Ras-like GTPases. It contains the four associated with diverse cellular processes, conserved elements that are typically found in Jürgen A. W. Heymann* and including the release of transport vesicles [as in the smaller Ras-like GTPases: the P-loop (G1 Jenny E. Hinshaw -mediated endocytosis (CME)], fusion motif), switch-I (G2), switch-II (G3), and Laboratory of Cell Biochemistry and Biology, NIH- and fission of mitochondria, division of the motif involved in base and nucleotide NIDDK, Bethesda, MD 20892, USA chloroplasts and peroxisomes, cell division, and binding (G4) (Reubold et al., 2005; Praefke and *Author for correspondence resistance to viral infections. Corresponding McMahon, 2004) (supplementary material ([email protected]) with their roles in a broad range of cellular Fig. S1A). In addition, the GTPase Journal of Cell Science 122, 3427-3431 functions, dynamins are found in all eukaryotic domain contains dynamin-specific sequences Published by The Company of Biologists 2009 doi:10.1242/jcs.051714 phyla (panel 3a in the poster). In this article and between G2 and G3, and downstream of the its accompanying poster, we present selected G4 motif; these sequences might add Supplementary material available online at aspects of what is known about individual regulatory functionality (Mears et al., 2007) http://jcs.biologists.org/cgi/content/full/122/19/3427/DC1 members of this superfamily in the context of (supplementary material Fig. S1B). The middle their structure, function, interaction partners and domain lacks similarity to established structural The superfamily of dynamins includes classical roles in diseases. motifs but contains a predicted coiled-coil dynamins and dynamin-related . region and has been shown to be crucial for the Classical dynamins are proteins that share GTPase is not enough self-assembly of human dynamin-1. The GED sequence similarity with the first described Three domains – GTPase domain, middle contains two predicted coiled-coil regions, is dynamin, which is a large GTPase with five domain and GTPase-effector domain (GED) – also involved in self-assembly and has been characteristic domains. Dynamin-related form the core of all dynamins (panel 1a in the shown to increase GTPase activity upon proteins differ from classical dynamins in that poster). The GTPase domain is the key dynamin self-assembly (Ramachandran et al., they contain, at a minimum, three of the five signature of dynamins and resembles that of 2007).

Dynamins at a Glance jcs.biologists.org Jürgen A. W. Heymann and Jenny E. Hinshaw

1a: Domain structure of dynamins 3a: Phylogenetic tree of dynamins 3b: Domain structure of selected dynamins 3c: Cellular function

Mitochondrial fusion Classical dynamins: five conserved domains Dynamin-1 GTPase Middle PH GED PRD Vesiculation Chloroplast fission 1 864 GTPase Middle PH GED PRD DRP2A Vesiculation (plant) Vesiculation; 1 914 plant cytokinesis Dynamin-related proteins: three core domains DRP1A Cytokinesis (plant) GTPase Middle GED 1 610 XX OPA1 MTS M Mitochondrial fusion 1 960

1b: Dynamin domain interactions DRP5B Chloroplast fission 1 808 Mitochondrial fusion Journal of Cell Science SH3 domains MFN1 M M Mitochondrial fusion 1 741 Dynamin-1 Vesicle budding GTPase Middle PH GED PRD Mx1 Antiviral activity 1 662 Antiviral activity Mitochondrial fission DRP3A 1 777 (plant)

DRP1 B Mitochondrial fission Mitochondrial and 1 736 peroxisomal fission Vacuolar and peroxisomal Vacuolar and 0.5 Vps1 peroxisomal fission 1 678 fission (yeast) Consensus tree from Bayesian analysis (unrooted; alignment of 45 dynamin sequences; 670 residues). Scale bar: substitutions per site. Branch values: posterior probabilities. X Cleavage site Interaction model Section of dynamin 3D reconstruction 4: Dynamins and mitochondrial dynamics (in humans) 5: Vesiculation by classical dynamins Model is derived from PRD-less dynamin-1 by electron microscopy, and combines data from Fusion Fission Clathrin-mediated endocytosis structural and biochemical studies. Solid and dashed lines indicate proposed connectivity Dynamin-mediated between dynamin domains at different planes. The location of the PRD remains to be determined. membrane fission

GDP+Pi GTP

2: Dynamins and diseases Plasma membrane OPA1 FIS1 DRP1 mutation Associated disease MFN2 Clathrin coat R369Q,W E560K S619L,W G358R Centronuclear myopathy V625del T859_I860del PtdIns(4,5)P2 E368K R465W A618T Dynamin-2* GTPase Middle PH GED PRD (human) IM Fis1 OPA1 Endophilin 1 K554fs 864 Charcot-Marie-Tooth MFN1 Dynamin Lipid IM Dynamin + GTP G533C K562E K562del type B OM D555_E557del K559del L570H OM 7: Partners of human dynamins Mitofusin 2 Charcot-Marie-Tooth GTPase Middle M M GED type 2A, hereditary motor (human) Caveolin SHANK1 and sensory neuropathy 1 757 6: Partners of ‘mitochondrial’ dynamins Modifiers SNX9 (HMSN) type VI Nostrin F-BAR–SH3 Human Fusion Fission PARL BAR-SH3 ASH Amphiphysin-2 OPA1 Autosomal dominant Dynamin-2 MTS M GTPase Middle GED SUMO1 SENP5 SH3 optic atrophy, deafness MFN1 FIS1 (human) PKA Amphiphysin 1 960 Paraplegin Other Endophilin-A3 Calcineurin SRC A395D MFN2 CDK1 DRP1 Endophilin-A2 GTPase Middle B GED Neonatal lethal YME1L CaMKI (human) ERK2 1 736 OPA1 DRP1 Calcineurin Cortactin R256L Dynamin-1 Dynamin-1 Exercise-induced Saccharomyces CDK5 Dynamin-3 GTPase Middle PH GED PRD Ugo1 Mdv1 (canine) collapse cerevisiae Modifier Intersectin 1 864 HOMER Membrane Pcp1 Fzo1 Caf4 Fis1 NCK1 FBP17 protein + Mutation; + Nonsense mutation; HMSN Vl mutation ABP1 Syndapin-3 Mgm1 Adaptor Dnm1 *Amino acid position based on splice form 1 (accession no. NP_001005360). Endophilin-A1 TUBA Syndapin-1

Abbreviations: At, Arabidopsis thaliana; B, B-domain; BAR, BIN1-Amphiphysin-RVS167 homology region; Ce, targeting sequence; OM, outer mitochondrial membrane; OPA, optical atrophy; Os, Oryza sativa; PH, pleckstrin-homology Caenorhabditis elegans; Cr, Chlamydomonas reinhardtii; Dd, Dictyostelium discoideum; Dm, Drosophila melanogaster; Dr, domain; PRD, proline-rich domain; PtdIns(4,5)P2, phosphatidylinositol (4,5)-bisphosphate; Sc, Saccharomyces cerevisiae; Danio rerio; DRP, dynamin-related protein; F-BAR, FER-CIP4 homology region; FIS1, fission 1; GED, GTPase-effector domain; SH3, Src-homology 3 domain; Sp, Schizosaccharomyces pombe; Vps, vacuolar protein sorting. Hs, Homo sapiens; IM, inner mitochondrial membrane; M, transmembrane segment; MFN, mitofusin; MTS, mitochondrial- © Journal of Cell Science 2009 (122, pp. 3427-3431)

(See poster insert) 3428 Journal of Cell Science 122 (19)

Classical dynamins harbor two additional internalization of caveolae (Praefcke and for fission. Dnm1 also contributes to the domains that dynamin-related proteins typically McMahon, 2004). In CME, the interplay division of peroxisomes in yeast, a process that lack: a highly conserved pleckstrin-homology between clathrin assembly, the recruitment of is mainly orchestrated by the dynamin Vps1. (PH) domain that confers binding to negatively proteins with membrane-remodeling activities The finding that dynamins are involved in the charged via its flexible regions (Ferguson and the action of dynamin leads to invagination division of both of these organelles corroborates et al., 1994) (supplementary material of clathrin-coated buds and vesiculation. GTP- the notion that the activities of peroxisomes and Fig. S2A,B) and a proline-rich domain (PRD) hydrolysis-induced conformational changes in mitochondria are fundamentally connected that is the binding site for proteins that interact dynamin might then drive constriction of the (Motley et al., 2008). Vps1 is also involved in with dynamins via Src-homology 3 (SH3) bud neck to the point that spontaneous fission the fission of yeast vacuoles (Peters et al., 2004). domains. Several of the dynamin-related at the neck, and release of the vesicle, occurs In plants, a combination of prokaryotic and proteins vary in their domain structure to (panel 5 in the poster). Alternatively, the eukaryotic proteins assists in the division of accommodate for specific functional release of dynamin from the membrane chloroplasts. DRP5B is the dynamin-related requirements; for example, some dynamin- following constriction of the bud neck might eukaryotic protein that facilitates division from related proteins contain membrane-spanning facilitate fission of the lipid tube (Bashkirov the outside of chloroplasts (Miyagishima et al., regions or organelle-targeting sequences (panels et al., 2008). Furthermore, it has been proposed 2008). Finally, members of the DRP3 protein 3a-c in the poster). that actin dynamics could be involved in the family are thought to regulate the fission of both Compared with Ras-GTPases, the GTPase fission and release of budding vesicles (Itoh mitochondria and peroxisomes in plants domain of classical dynamins has a lower et al., 2005; Shin et al., 2008). (Fujimoto et al., 2009). affinity for nucleotides and displays higher In plants, the dynamin-1 homolog dynamin- The observation that dynamins can be hydrolysis rates. In addition, the GTPase related protein 2A (DRP2A) interacts with involved in more than one cellular process domain of dynamins exhibits cooperativity clathrin-binding partners, but there is no direct suggests that there are mechanisms in place that of GTP hydrolysis upon dynamin evidence that DRP2A is involved in might regulate their targeting to specific oligomerization. Thus, in vitro rates of endocytosis. Instead, DRP2A mediates Golgi- organelles and modulate their function. hydrolysis increase by one to two orders vacuole trafficking and has been shown to of magnitude when dynamin self-assembles localize to the forming cell plate (Fujimoto et al., Organelle fusion into helical arrays around lipid tubes (Song 2008). By contrast, Arabidopsis DRP1C, a In animals, the fusion of mitochondria involves et al., 2004). Interactions between the GTPase protein of the DRP1 family that lacks both at least two steps: fusion of the outer domain, the middle domain and the GED drive the PH domain and the PRD, localizes to the mitochondrial membrane via the membrane- this self-assembly process, whereas the PH division plane and the plasma membrane, and is anchored dynamins mitofusin 1 (MFN1) and domain provides affinity for lipid (panel 1b in thought to take part in clathrin-mediated MFN2, and fusion of the inner membrane via the poster). Upon hydrolysis of GTP, dynamin membrane dynamics (Konopka et al., 2008). optic atrophy 1 homolog (OPA1) (panel 4 in the undergoes a conformational change that leads Although budding yeast utilizes CME and poster). In budding yeast, the OPA1 ortholog to a decrease in the helix diameter, thereby expresses proteins that are homologous to Mgm1 is essential for fusion of the inner constricting and twisting the enclosed lipid mammalian dynamin-binding proteins [such as mitochondrial membrane but also seems to be

Journal of Cell Science tube (Danino et al., 2004; Roux et al., 2006) yeast homologs of the dynamin partner involved in the fusion of the outer membrane, (panel 5 in the poster). These observations amphiphysin (Rvs161p, Rvs167p)], no yeast because cells that lack Mgm1 do not undergo suggest that dynamin translates the scalar dynamin proteins have been shown to be mitochondrial fusion (Sesaki et al., 2003). chemical process of GTP hydrolysis into a involved in CME. Mitochondrial fusion in yeast also requires the vectorial physical force – that is, it exhibits The important differences between CME mitofusin ortholog fuzzy onions 1 (Fzo1). mechano-enzymatic properties (Hinshaw, events that are observed in animals, plants and Mitofusins are thought to form homo- or hetero- 2000). In vitro, multiple rounds of GTP yeast suggest that the role and requirement of oligomers through C-terminal heptad repeat hydrolysis lead to the disassembly of dynamin dynamins in this process is not universal. regions, and tether adjacent mitochondria in oligomers and their release from the lipid what might be the first step of mitochondrial bilayer (Danino et al., 2004). The results of Organelle fission fusion (Benard and Karbowski, 2009). recent light-microscopy studies suggest that In animals and budding yeast, the dynamin- Mammalian OPA1 and yeast Mgm1 each exist dynamin alone could be sufficient for related proteins DRP1 and Dnm1, respectively, in two forms, a membrane-bound form and a membrane fission in vitro (Bashkirov et al., mediate fission of mitochondria (panel 4 in the diffusible form, both of which are required for 2008; Pucadyil and Schmid, 2008). poster). These proteins lack a PRD and PH mitochondrial fusion; these are produced by domain but contain a B-domain that is located proteolytic processing of the proteins once they Dynamins mediate more than between the middle domain and the GED, and are targeted to the mitochondrial membrane. endocytosis that is devoid of any specific structural features Purified yeast Mgm1 protein has been shown to The domain architecture of dynamins and (panel 3b in the poster). Despite the absence of a assemble into low-order oligomers and displays dynamin-related proteins provides the structural PH domain, Dnm1 binds preferentially to GTPase activity. Although Mgm1 lacks a PH basis for these proteins to carry out a large negatively charged lipids and, similar to human domain, it preferentially binds to negatively variety of essential cellular functions. dynamin-1, assembles into helical structures charged phospholipids that are typically found around lipid tubes. Notably, the dimensions of in mitochondrial membranes, which suggests Vesicle budding the diameter of Dnm1 helical assemblies on that Mgm1 contains a lipid-binding motif In animals, classical dynamins facilitate lipid tubes (~110 nm) match those of (Meglei and McQuibban, 2009). Furthermore, vesicle budding in CME and are required for mitochondrial constriction sites (Ingerman the dynamins of the inner mitochondrial other events such as budding of vesicles from et al., 2005), which suggests that Dnm1 spirals membrane, together with scaffolding proteins the recycling endosome and Golgi, and for the could encompass mitochondrial sites destined such as prohibitins, are thought to be involved in Journal of Cell Science 122 (19) 3429

the maintenance of cristae morphology, possibly Not a lone ranger – dynamin partners least three proteases (PARL, paraplegin and by assembling into higher-order structures Although there is a great deal of information Yme1) might be involved in the constitutive (Merkwirth and Langer, 2008). Because available regarding the function of dynamins, processing of OPA1 once it is inserted into the mitochondria are not only the cellular understanding exactly how they operate in the mitochondrial membrane. Increased cleavage powerhouse but are also central for apoptosis, different cellular settings remains challenging of OPA1 coincides with mitochondrial tight regulation of cytochrome-c pools via owing to the complexity of their interactions fragmentation, which indicates that OPA1 can cristae junction morphology and mitochondrial with the cellular machinery. Dynamins are be inactivated by inducible proteases (Griparic dynamics is indispensable; therefore, regulation intrinsic GTPases that require neither exchange et al., 2007). of mitochondrial fusion and fission events factors to replace GDP nor other proteins to probably involves many other components. hydrolyze GTP. Nonetheless, their activity Dynamin-binding partners Dynamins that are associated with depends on protein-protein interactions that are In the case of classical dynamins, binding mitochondrial fusion have not been found in based on oligomerization and self-assembly. In partners interact with the PRD of dynamin plants, which suggests that this process might addition to dynamin-dynamin and dynamin- through SH3 domains. Dynamin-related occur by a different mechanism (Sheahan et al., lipid interactions, most dynamins have been proteins lack a PRD and bind by other as-yet- 2005). Although a Fzo1-like protein (FZL) has shown to interact with an ever-expanding unknown mechanisms. Most binding partners been identified, it was shown to be involved in number of accessory proteins (Kruchten and mediate interactions either with other proteins or the determination of thylakoid and chloroplast McNiven, 2006; Kim and Chang, 2006) (panels with membranes. morphology, but not that of mitochondria (Gao 6 and 7 in the poster). Dynamin partners can be At the outer mitochondrial membrane, the et al., 2006). grouped into two distinct classes: modifiers and proteins Mdv1 and Caf4 link the mitochondrial binding partners. dynamin Dnm1 to the integral membrane protein Plant cytokinesis Fis1 for mitochondrial fission in yeast. Mdv1 or In Arabidopsis, members of the DRP1 protein Dynamin modifiers Caf4 binds to Fis1 through a helix-loop-helix family (known as the phragmoplastin family in Dynamin modifiers include kinases, motif and to oligomeric Dnm1 through a WD40 soybean) are involved in cytokinesis and cell phosphatases, ubiquitin ligases, deubiquity- repeat, thereby connecting soluble Dnm1 to the expansion. They are thought to generate lases, small ubiquitin-like modifier (SUMO) outer mitochondrial membrane (Naylor et al., dumbbell-shaped tubular structures located at ligases and proteases, and constitutively active 2006; Zhang and Chan, 2007). The the cell plate, which is the zone that generates a or induced proteases. These enzymes regulate mitochondrial outer membrane protein Ugo1, for new cell wall between dividing cells. Such dynamin activity within the complex network which a mammalian ortholog has not been tubulation would prevent the fusion of Golgi- of dynamin-protein interactions. identified, physically links Mgm1 and Fzo1 derived vesicles into a large vacuole and would Human dynamin-1 undergoes reversible (Okamoto and Shaw, 2002; Hoppins et al., instead give rise to the outward-growing, phosphorylation at two serine residues in its 2009). Another example of a dynamin-binding dividing cell plate (Verma and Hong, 2005). PRD. Dephosphorylation of dynamin-1 occurs partner is actin-binding protein 1 (ABP1), which during synaptic-vesicle endocytosis in nerve binds to human dynamin-2 through its SH3 Antiviral activity terminals and is stimulus-dependent. It has domains and to F-actin through its actin-

Journal of Cell Science Members of the Mx GTPase proteins form a been shown to be associated with the binding domains. By linking the actin separate group within the dynamin superfamily. recruitment of syndapin 1 to the endocytic cytoskeleton and endocytic proteins, ABP1 is They have the three core dynamin domains and protein complex, in which syndapin 1, an thought to initiate the internalization of B-cell the ability to form oligomers, but they also F-BAR protein, possibly has membrane- receptors, thereby regulating antigen processing contain unique sequence motifs. Mx proteins are tubulating function (Anggono et al., 2006). and presentation (Onabajo et al., 2008). found in most vertebrate species and confer Similarly, DRP1 is reversibly phosphorylated The majority of binding partners of classical resistance to a variety of viruses following the by at least three kinases (CaMKI, CDKI and dynamins contain BAR or F-BAR domains and, induction of their expression in response to PKA), and these modifications are thought to therefore, have membrane-bending or -sensing interferon. The antiviral mechanism is thought regulate mitochondrial dynamics and cell- properties (Heath and Insall, 2008). to occur through the binding of Mx proteins to death pathways (Han et al., 2008). Amphiphysin and endophilin are two examples essential viral components. Mx proteins are not Furthermore, DRP1 has been shown to of BAR proteins that tubulate lipids and bind only found in the cytoplasm but also at nuclear undergo SUMOylation by conjugation to to dynamin. Amphiphysin is thought to target sites, such as the nuclear pores and inside the SUMO1, a modification that is associated with dynamin to clathrin-coated pits and to nucleus, which suggests that they might have a an increase in DRP1-mediated mitochondrial modulate dynamin self-assembly (Ren et al., role in regulating the transport of ribonucleo- fission. This modification is removed by the 2006). Endophilin is thought to recruit dynamin protein particles between nucleus and cytoplasm protease SENP5 (Zunino et al., 2007). Other to sites of sensed or induced curvature such as (Haller et al., 2007). dynamins are regulated by proteolytic events. those found at the nascent necks of clathrin- In yeast, the integral membrane protein Fzo1 coated pits (Gallop et al., 2006). Notably, Other controls fusion of the mitochondrial outer members of both the BAR and F-BAR families In addition to the dynamins described above, membrane. Cellular levels of Fzo1 are bind not only to dynamin but also to Wiskott- proteins that are distantly related to dynamins regulated through ubiquitin-dependent Aldrich proteins (WASP, N-WASP), which are have been identified in eukaryotes [guanylate- targeting of Fzo1 for proteasome-mediated scaffolding proteins that recruit actin and the binding proteins (Ghosh et al., 2006)] and in degradation (Cohen et al., 2008). As in the actin-related protein 2/3 (ARP2/3) complex. prokaryotes [bacterial dynamin-like proteins case of Mgm1 in yeast (Sesaki et al., 2006), Collectively, these findings indicate that (Low and Lowe, 2006)]. Although the X-ray proteolysis has also been implied in post- dynamin-mediated vesiculation and actin structures of these proteins have been solved, translational processing and regulation of the polymerization are intricately linked (Takenawa their function remains unknown. mammalian mitochondrial dynamin OPA1. At and Suetsugu, 2007). 3430 Journal of Cell Science 122 (19)

When things fall apart – dynamins and speculated that affected nerve cells in the optical transient and probably vary with cell type, diseases or auditory system are much more susceptible to tissues, species or metabolic state. Finally, much The fact that dynamins are involved in key disturbances in the arrangement of mitochondria has to be learned about how expression levels, cellular processes suggests that mutations in than the cells in other tissues, and that the distribution of splice variants and the activities dynamins, or alterations in their expression, resulting changes in bioenergetics and of dynamins are regulated. could interfere with their specific functions and the induction of apoptosis cause the observed The laboratory is supported by the intramural research might be associated with diseases. The earliest detrimental effects on vision and hearing program of the NIDDK, National Institutes of Health. evidence for the involvement of dynamins in (Olichon et al., 2006). Deposited in PMC for release after 12 months. human disease came from studies that The importance of organelle dynamics for investigated the molecular origins of normal physiology is also highlighted by the References myopathies. Genetic analysis revealed that finding that a single mutation in the middle Amati-Bonneau, P., Milea, D., Bonneau, D., Chevrollier, mutations in human dynamin-2 were connected domain of the human dynamin DRP1 was A., Ferre, M., Guillet, V., Gueguen, N., Loiseau, D., Crescenzo, M. A., Verny, C. et al. (2009). OPA1- with defects in endocytosis. On the basis of associated with a severe defect in the fission of associated disorders: phenotypes and pathophysiology. Int. clinical presentation, it is possible to discern two mitochondria and peroxisomes, and resulted in J. Biochem. Cell Biol. 41, 1855-1865. Anggono, V., Smillie, K. J., Graham, M. E., Valova, V. basic types of disease phenotypes: centronuclear neonatal lethality (Waterham et al., 2007). In A., Cousin, M. A. and Robinson, P. J. (2006). Syndapin I myopathy (CNM), a slow-progressing disease contrast to the late-onset progressive disorders is the phosphorylation-regulated dynamin I partner in of the muscle, and Charcot-Marie-Tooth type B described above, this DRP1-dependent disorder synaptic vesicle endocytosis. Nat. Neurosci. 9, 752-760. Bashkirov, P. V., Akimov, S. A., Evseev, A. I., Schmid, S. (CMTB), comprising a diverse group of developed rapidly and led to defects in multiple L., Zimmerberg, J. and Frolov, V. A. (2008). GTPase peripheral neuropathies. The CMTB phenotype tissues. cycle of dynamin is coupled to membrane squeeze and is exclusively caused by mutations located in the Human dynamin-1 plays an important role in release, leading to spontaneous fission. Cell 135, 1276- 1286. dynamin PH domain, which suggests that synaptic-vesicle endocytosis and in neurotrans- Benard, G. and Karbowski, M. (2009). Mitochondrial the mutated protein expressed by patients with mission. A mutation in the GTPase domain of fusion and division: regulation and role in cell viability. this disease is defective in dynamin-lipid canine dynamin-1 has been shown to cause the Semin. Cell Dev. Biol. 20, 365-374. Bitoun, M., Maugenre, S., Jeannet, P. Y., Lacene, E., binding. By contrast, mutations in the dynamin condition of reversible collapse, which is Ferrer, X., Laforet, P., Martin, J. J., Laporte, J., middle domain and in the far C-terminal portion caused by a deficiency in sustained synaptic Lochmuller, H., Beggs, A. H. et al. (2005). Mutations in of the PH domain lead to the CNM phenotype, transmission during heightened neural activity. dynamin 2 cause dominant centronuclear myopathy. Nat. Genet. 37, 1207-1209. which suggests that there are defects in dynamin Dysfunction of dynamin-1 is now considered a Bitoun, M., Bevilacqua, J. A., Eymard, B. and Prudhon, assembly in patients that carry this mutation candidate theory to explain the syndrome of B. (2009). A new centronuclear myopathy phenotype due to (Zuchner et al., 2005; Bitoun et al., 2005; Fabrizi exercise-induced collapse (EIC) in Labrador a novel dynamin 2 mutation. Neurology 72, 93-95. Cohen, M. M., Leboucher, G. P., Livnat-Levanon, N., et al., 2007) (panel 2 in the poster). Interestingly, retrievers (Patterson et al., 2008). Glickman, M. H. and Weissman, A. M. (2008). Ubiquitin- a recently discovered mutation that is associated Finally, it has been shown that the expression proteasome-dependent degradation of a mitofusin, a critical levels of dynamin-1 are decreased in the brains regulator of mitochondrial fusion. Mol. Biol. Cell 19, 2457- with a CNM phenotype maps to the GED, which 2464. suggests a more complex relationship between of patients with Alzheimer’s disease (Yao et al., Danino, D., Moon, K. H. and Hinshaw, J. E. (2004). the location of the dynamin-2 mutation and 2003). It has been proposed that amyloid-β Rapid constriction of lipid bilayers by the mechanochemical enzyme dynamin. J. Struct. Biol. 147, 259-267.

Journal of Cell Science disease phenotype (Bitoun et al., 2009). peptides, the expression of which is reportedly Fabrizi, G. M., Ferrarini, M., Cavallaro, T. and Cabrini, Mutations in the dynamin-related protein increased in the brains of these patients, might I. (2007). Two novel mutations in dynamin-2 cause axonal MFN2 are associated with Charcot-Marie-Tooth induce the decrease in dynamin levels by Charcot-Marie-Tooth disease. Neurology 69, 291-295. Ferguson, K. M., Lemmon, M. A., Schlessinger, J. and disease CMT type 2A, and with hereditary stimulating calpain-mediated cleavage of Sigler, P. B. (1994). Crystal structure at 2.2 A resolution of motor and sensory neuropathy type VI. Both of dynamin-1 (Kelly et al., 2005). In addition, the pleckstrin homology domain from human dynamin. Cell these diseases lead to axonal degeneration, and there is evidence that late-onset Alzheimer’s 79, 199-209. Fujimoto, M., Arimura, S. I., Nakazono, M. and the latter is coupled with optical neuropathy. In disease is associated with a single nucleotide Tsutsumi, N. (2008). Arabidopsis dynamin-related protein these diseases, MFN2 mutations are located in polymorphism in intron 1 of dynamin-2, and DRP2B is co-localized with DRP1A on the leading edge of the GTPase domain and in the C-terminal that the level of dynamin-2 mRNA is reduced in the forming cell plate. Plant Cell Rep. 27, 1581-1586. Fujimoto, M., Arimura, S. I., Mano, S., Kondo, M., coiled-coil domain, which is implicated in patients with dementia by an as-yet-unknown Saito, C., Ueda, T., Nakazono, M., Nakano, A., binding to the coiled-coil domain of MFN1. mechanism. The decrease in dynamin Nishimura, M. and Tsutsumi, N. (2009). Arabidopsis This suggests that the mutated protein is expression is thought to be associated with an dynamin-related proteins DRP3A and DRP3B are functionally redundant in mitochondrial fission but have defective either in its GTPase activity or in its increase in the levels of amyloid-β, similar to the distinct roles in peroxisomal fission. Plant J. 58, 388-400. capacity to tether to fusion partners such as effect observed with a dysfunctional dynamin-2 Gallop, J. L., Jao, C. C., Kent, H. M., Butler, P. J., Evans, MFN1 during mitochondrial fusion (Verhoeven mutant, thereby possibly generating a vicious P. R., Langen, R. and McMahon, H. T. (2006). Mechanism of endophilin N-BAR domain-mediated et al., 2006). It is thought that mutations in cycle that could contribute to the observed membrane curvature. EMBO J. 25, 2898-2910. MFN2 perturb mitochondrial dynamics or amyloid pathology (Kamagata et al., 2009). Gao, H., Sage, T. L. and Osteryoung, K. W. (2006). FZL, an FZO-like protein in plants, is a determinant of thylakoid possibly alter the axonal transport of and chloroplast morphology. Proc. Natl. Acad. Sci. USA mitochondria. Conclusion 103, 6759-6764. The most common origin of optic atrophy, A molecular understanding of how dynamins Ghosh, A., Praefcke, G. J., Renault, L., Wittinghofer, A. and Herrmann, C. (2006). How guanylate-binding known as autosomal dominant optic atrophy operate has been hampered by the fact that is has proteins achieve assembly-stimulated processive cleavage (ADOA), is caused by loss-of-function been very difficult to obtain structural of GTP to GMP. Nature 440, 101-104. mutations in the mitochondrial dynamin OPA1 information at the atomic level even for Griparic, L., Kanazawa, T. and van der Bliek, A. M. (2007). Regulation of the mitochondrial dynamin-like and is associated with a progressive loss of individual domains. Dissecting the complex protein Opa1 by proteolytic cleavage. J. Cell Biol. 178, 757- vision. A subset of mutations that occur in the interaction networks in which dynamins are 764. GTPase domain of OPA1 are also linked to involved on a cellular level is also a daunting Haller, O., Stertz, S. and Kochs, G. (2007). The Mx GTPase family of interferon-induced antiviral proteins. deafness (Amati-Bonneau et al., 2009). It is task, because their partners are numerous, Microbes Infect. 9, 1636-1643. Journal of Cell Science 122 (19) 3431

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