Model for the Motor Component of Dynein Heavy Chain Based on Homology to the AAA Family of Oligomeric ATPases

Mócz, Gábor; Gibbons, I. R.

doi:10.1016/s0969-2126(00)00557-8

Cited by 93 publications

(83 citation statements)

References 54 publications

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“…The appearance of the head of dynein c supports the idea of a toroidal arrangement of domains suggested previously 12,13,21,33 . The head is also large enough to accommodate at least six AAA domains arranged in a planar ring, as described by a hypothetical atomic model of dynein 33 . However, this model predicts a similar appearance of the two faces and six-fold rotational symmetryneither is seen in our images.…”

Section: Discussionsupporting

confidence: 87%

“…4b, left), the docked linker occludes the central channel and the stem emerges from the head far from the stalk. Microtubule movement is initiated by tight binding to the tip of the stalk, which promotes a concerted conformational change in AAA1-4, thereby activating release of ADP and phosphate from AAA1, the probable site of ATP hydrolysis 33 . Rigid coupling between AAA1 and linker causes a rolling of the head towards the stem, which translates the microtubule by 15 nm under zero load conditions.…”

Section: Discussionmentioning

confidence: 99%

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Dynein structure and power stroke

Burgess

Walker

Sakakibara

et al. 2003

Nature

472

552

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Dynein ATPases are microtubule motors that are critical to diverse processes such as vesicle transport and the beating of sperm tails; however, their mechanism of force generation is unknown. Each dynein comprises a head, from which a stalk and a stem emerge. Here we use electron microscopy and image processing to reveal new structural details of dynein c, an isoform from Chlamydomonas reinhardtii flagella, at the start and end of its power stroke. Both stem and stalk are flexible, and the stem connects to the head by means of a linker approximately 10 nm long that we propose lies across the head. With both ADP and vanadate bound, the stem and stalk emerge from the head 10 nm apart. However, without nucleotide they emerge much closer together owing to a change in linker orientation, and the coiled-coil stalk becomes stiffer. The net result is a shortening of the molecule coupled to an approximately 15-nm displacement of the tip of the stalk. These changes indicate a mechanism for the dynein power stroke.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Dynein structure and power stroke

Burgess

Walker

Sakakibara

et al. 2003

Nature

472

552

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“…An N-terminal tail domain of the heavy chain, along with several associated polypeptides (the "stem" [31]), interacts directly or indirectly with the cargo, either an A-tubule of a flagellar doublet or a membranous organelle in the case of cytoplasmic dynein. A heavy chain also encompasses a series of 6 or 7 AAA (ATPases Associated with diverse cellular Activities) domains arranged in a ring [32][33][34][35][36][37], though only four of the AAA domains (P1 -P4) bind ATP [38,39]. The region apparently responsible for direct interaction with the track loops out from the motor domain between P4 and P5, forming a small globular domain at the end of an antiparallel coiled-coil [33,34], the "stalk" [31].…”

Section: Dyneinmentioning

confidence: 99%

Molecular motors: not quite like clockwork

Amos

2008

Cell. Mol. Life Sci.

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Models commonly used to explain the mechanism of myosin motors typically include a powerstroke that is attributed to a conformational change in the motor domain and amplified by a long leverarm that connects the motor domain to the cargo. Similar models have proved less enlightening in the case of microtubule motors, for which it may be more helpful to consider models involving thermally driven mechanisms.

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“…In these models, ATP hydrolysis induces movement of either the stalk, the tail or an flexible linker between the motor unit and the tail (8,9,11,13,14). However, none of these models directly predict how forces are transduced from the primary hydrolytic site to the rest of the rest of the domains.…”

mentioning

confidence: 99%

“…1) (7,8). Mocz and Gibbons (8) used homology modeling to construct the first structural model of dynein.…”

mentioning

confidence: 99%

A structural model reveals energy transduction in dynein

Serohijos

Chen

Ding

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Intracellular active transport is driven by ATP-hydrolyzing motor proteins that move along cytoskeletal filaments. In particular, the microtubule-associated dynein motor is involved in the transport of organelles and vesicles, the maintenance of the Golgi, and mitosis. However, unlike kinesin and myosin, the mechanism by which dynein converts chemical energy into mechanical force remains largely a mystery, due primarily to the lack of a highresolution molecular structure. Using homology modeling and normal mode analysis, we propose a complete atomic structure and a mechanism for force generation by the motor protein dynein. In agreement with very recent electron microscopy (EM) reconstructions showing dynein as a ring-shaped heptamer, our model consists of six ATPases of the AAA (ATPases associated with various cellular activities) superfamily and a C-terminal domain, which is experimentally known to control motor function. Our model shows a coiled coil spanning the diameter of the motor that accounts for previously unidentified structures in EM studies and provides a potential mechanism for long-range communication between the AAA domains. Furthermore, normal mode analysis reveals that the subunits of the motor that contain the nucleotide binding sites exhibit minimal movement, whereas the rest of the motor is very mobile. Our analysis suggests the likely domain rearrangements of the motor unit that generate its power stroke. This study provides insights into the structure and function of dynein that can guide further experimental investigations into energy transduction in dynein.AAA ͉ homology modeling ͉ molecular motors ͉ electron microscopy ͉ ATP hydrolysis M otor proteins use energy derived from ATP hydrolysis to move along cytoskeletal filaments (1). In particular, the microtubule-associated molecular motor dynein is involved in the transport of organelles and vesicles, the maintenance of the Golgi, and mitosis (2, 3). Mutations in this protein have been implicated in neurodegenerative diseases (4) and polycystic kidney disease (5). Unlike the motor proteins kinesin and myosin, the mechanism by which dynein converts chemical energy into mechanical force remains largely a mystery. The primary reason for this is the lack of a high-resolution molecular structure. Cytoplasmic dynein is a large multisubunit complex (1.2 MDa) composed of two heavy chains (Ϸ0.5 MDa each) (6), making its structural characterization extremely challenging. In this study, we use homology modeling to propose a structure for the motor unit of the dynein heavy chain, which is the site for energy transduction and force generation (see Fig. 1a). Next, we perform normal mode analysis to determine the large-scale motions of the protein. Together, these results suggest a mechanism for both force generation and regulatory control in dynein.Sequence analysis of dynein's motor unit indicates that it consists of six concatenated AAA (ATPases associated with diverse cellular activities) subunits, an extended stalk that contains a microtubule bind...

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Model for the Motor Component of Dynein Heavy Chain Based on Homology to the AAA Family of Oligomeric ATPases

Cited by 93 publications

References 54 publications

Dynein structure and power stroke

Dynein structure and power stroke

Molecular motors: not quite like clockwork

A structural model reveals energy transduction in dynein

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