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CONTRIBUTORS

John A. Cooper Department of Cell Biology, Washington University, St. Louis, MO, 63110 Rodney J. Devenish Department of Biochemistry and Molecular Biology, and ARC Centre of Excellence in Microbial Structural and Functional Genomics, Monash University, Clayton Campus, Victoria, 3800, Australia Birthe Fahrenkrog M.E. Mu¨ller Institute for Structural Biology, Biozentrum, University of Basel, Klingelbergstrasse 70, 4056 Basel, Switzerland Sheng T. Hou Institute for Biological Sciences, National Research Council of Canada, Ottawa, Ontario, K1A 0R6, Canada Susan X. Jiang Institute for Biological Sciences, National Research Council of Canada, Ottawa, Ontario, K1A 0R6, Canada Irina M. Konstantinova Institute of Cytology, Russian Academy of Sciences, St. Petersburg, 194064, Russia Roderick Y. H. Lim M.E. Mu¨ller Institute for Structural Biology, Biozentrum, University of Basel, Klingelbergstrasse 70, 4056 Basel, Switzerland Alexey G. Mittenberg Institute of Cytology, Russian Academy of Sciences, St. Petersburg, 194064, Russia Mark Prescott Department of Biochemistry and Molecular Biology, and ARC Centre of Excellence in Microbial Structural and Functional Genomics, Monash University, Clayton Campus, Victoria, 3800, Australia Mary Ann Rempel Department of Environmental Sciences, University of California, Riverside, CA 92521

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Contributors

Francisco Rivero The Hull York Medical School and Department of Biological Sciences, University of Hull, Hull HU6 7RX, United Kingdom Andrew J. W. Rodgers Industrial Biotechnology Group, CSIRO Division of Molecular and Health Technologies, Clayton, Victoria, 3168, Australia Daniel Schlenk Department of Environmental Sciences, University of California, Riverside, CA 92521 David Sept Department of Biomedical Engineering and Center for Computational Biology, Washington University, St. Louis, MO, 63130 Robert A. Smith Division of Neuroscience and Biomedical Systems, Institute of Biomedical and Life Sciences, University of Glasgow, G12 8QQ, Scotland Anna S. Tsimokha Institute of Cytology, Russian Academy of Sciences, St. Petersburg, 194064, Russia Katharine S. Ullman Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112 Mirjam Zegers Department of Surgery, University of Chicago, Chicago, IL 60637

C H A P T E R

O N E

The Structure and Function of Mitochondrial F1F0-ATP Synthases Rodney J. Devenish,* Mark Prescott,* and Andrew J. W. Rodgers† Contents 1. Introduction 2. Mitochondrial ATP Synthase 2.1. Overview of the structure and subunit composition 2.2. Rotary catalysis 2.3. The F1 sector 2.4. The peripheral/‘‘Stator’’ stalk 2.5. The F0 sector 3. Supramolecular ATP Synthase 3.1. Introduction 3.2. Dimers and oligomers 3.3. Subunits relevant to dimer formation 3.4. The arrangement of mtATPase in mitochondrial membranes 3.5. The role of mtATPase oligomerisation 3.6. Is oligomerization regulated in vivo? 3.7. Supramolecular structures involving other respiratory complexes? 4. Extra-Mitochondrial Expression of F1F0-ATP Synthase 4.1. Introduction 4.2. How might F1F0 ATP synthase get to the plasma membrane? 4.3. The function of coupling factor 6 as a vasoconstrictor: Detachment and reattachment of an F0 component of eAS? 4.4. Multiple receptor functions of subunit b 4.5. The inhibitor action of IF1 can be demonstrated for eAS complexes 5. Concluding Remarks References

* {

2 3 3 5 7 12 18 23 23 23 25 29 31 34 35 36 36 37 39 40 42 42 43

Department of Biochemistry and Molecular Biology, and ARC Centre of Excellence in Microbial Structural and Functional Genomics, Monash University, Clayton Campus, Victoria, 3800, Australia Industrial Biotechnology Group, CSIRO Division of Molecular and Health Technologies, Clayton, Victoria, 3168, Australia

International Review of Cell and Molecular Biology, Volume 267 ISSN 1937-6448, DOI: 10.1016/S1937-6448(08)00601-1

#

2008 Elsevier Inc. All rights reserved.

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Rodney J. Devenish et al.

Abstract We review recent advances in understanding of the structure of the F1F0-ATP synthase of the mitochondrial inner membrane (mtATPase). A significant achievement has been the determination of the structure of the principal peripheral or stator stalk components bringing us closer to achieving the Holy Grail of a complete 3D structure for the complex. A major focus of the field in recent years has been to understand the physiological significance of dimers or other oligomer forms of mtATPase recoverable from membranes and their relationship to the structure of the cristae of the inner mitochondrial membrane. In addition, the association of mtATPase with other membrane proteins has been described and suggests that further levels of functional organization need to be considered. Many reports in recent years have concerned the location and function of ATP synthase complexes or its component subunits on the external surface of the plasma membrane. We consider whether the evidence supports complete complexes being located on the cell surface, the biogenesis of such complexes, and aspects of function especially related to the structure of mtATPase. Key Words: Cristae, Dimers, External ATP synthase (eAS), Mitochondrial ATP synthase (mtATPase), Mitochondrial inner membrane, Peripheral or ‘‘stator’’ stalk. ß 2008 Elsevier Inc.

1. Introduction F1F0-ATP synthases are enzyme complexes found in eubacterial plasma membranes, chloroplast thylakoid membranes and the inner membranes of mitochondria. Their function is to harness energy from a gradient of protons (or sodium ions, in some bacteria) across the membrane to synthesise ATP from ADP and Pi. This chapter will review recent advances in the structure and function of mitochondrial ATP synthase (mtATPase). We focus on three areas: (i) the emerging understanding of the structure of the peripheral, or stator, stalk and the subunits comprising it; (ii) the relationship between oligomeric ATP synthase complexes and mitochondrial cristae; and (iii) the extra-mitochondrial location and function of enzyme complexes apparently equivalent to ATP synthase. We draw principally on studies in yeast and mammalian cells (bovine and rat), but refer to relevant studies of the bacterial enzyme particularly in relation to structure and function of the complex. The assembly of mtATPase is not considered here as it has been a major focus of a recent review (Ackerman and Tzagoloff, 2005).

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Structure and Function of mtATPases

2. Mitochondrial ATP Synthase 2.1. Overview of the structure and subunit composition F1F0-ATP synthases are traditionally viewed as consisting of a soluble portion (the F1 sector), where the sites catalysing the formation and hydrolysis of ATP are located, and a membrane-bound portion (the F0 sector), which functions as a proton channel (Fig. 1.1). Table 1.1 shows the subunit a

OSCP

b

b

d

F6 g e d

C10

b

a +e,f,g, A6L

Figure 1.1 The subunit organization in mtATPase. Subunits are labelled. F1 is the globular domain made of subunits a, b and the three central stalk subunits, g, d and e.The F0 domain is comprised of the subunit c ring (10 copies in yeast), subunit a, and the peripheral stalk subunits b, d, F6(h) and OSCP. The so-called minor subunits [e, f, g, and A6L(8)] are not shown individually, but they all span the membrane and are probably present in a 1:1:1:1 stoichiometry.The rotor is made up of the central stalk and the c-ring. The remainder of the subunits make up the stator. F1 is shown with one a subunit removed for clarity.The inhibitor protein (IF1) is also not shown; it binds in a catalytic a/b interface near the bottom of (ab)3. [This article was published in Biochimica et Biophysica Acta,Vol. 757,Walker, J. E. and Dickson,V. K.,The peripheral stalk of the mitochondrial ATP synthase, 286^296, Copyright Elsevier (2006).]

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Table 1.1 Subunit composition, genetic specification and stoichiometry of mtATPase from yeast and mammalian cells Mitochondria

Bacteria (E. coli) Subunit

Genea

Subunitb

ATP1 ATP2 ATP3

a

a b g (see OSCP) d e Su6

a b g (see OSCP) d e Su6m

1 1 1

b c

B Su9

b Su9

1 10

A6Lm

1

OSCP d e f g F6

1 1 1 (2d ) 1 1 1 1 ? 1 1

Sector Subunit

F1

a b g d e

F0

Mammalian Stoichiometryc

Yeast

Su8 OSCP D E F G H i/j K INH STF1 (9 kDa) STF2 (15 kDa) STF3

ATP16 ATP15 ATP6 m (oli2) ATP4 ATP9m (olil) ATP8m (aap1) ATP5 ATP7 ATP21 ATP17 ATP20 ATP14 ATP18 ATP19 INH1 STF1

IF1

3 3 1

STF2

1

STF3

?

Subunits are aligned horizontally based on sequence or functional homology. The bacterial (E. coli) subunits are shown for comparison with mtATPase subunits. a Genes are in nuclear DNA of Saccharomyces cerevisiae, except those marked with m, which are in mitochondrial DNA. References for individual subunits are as follows: ATP1, Takeda et al., 1986; ATP2, Takeda et al., 1985; ATP3, Paul et al., 1994; ATP16, Giraud and Velours, 1994; ATP15, Guelin et al., 1993; ATP6 (oli2), Macino and Tzaqgoloff, 1980; ATP4, Velours et al., 1988; ATP9 (oli1), Hensgens et al., 1979; Macino and Tagoloff, 1979; ATP8 (aap1), Macreadie et al., 1983; ATP5, Uh et al., 1990; ATP7, Norais et al., 1991; ATP21, Arnold et al., 1997; ATP17, Spannagel et al., 1997; ATP20, Boyle et al., 1999; ATP14, Arselin et al., 1996; ATP18, Arnold et al., 1999 and Vaillier et al., 1999; ATP19, Arnold et al., 1998; INH1, Ichikawa et al., 1990; STF1, Akashi et al., 1988; STF2, Yoshida et al., 1990; STF3, Hong and Pedersen, 2002.

Structure and Function of mtATPases

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composition of mtATPase. In the mitochondrial enzyme, F1 is composed of three copies of each of subunits a and b, and one each of subunits g, d and e. The inhibitor protein (IF1) is not traditionally considered as an F1 subunit, but we will consider it here in this context because the available evidence suggests that when bound to mtATPase it associates principally with F1 subunits. F1 subunits g, d and e constitute the ‘‘central’’ stalk of mtATPase. F0 consists of a subunit c ring (comprising 10 copies in the case of the yeast enzyme, but varying to up to 14 copies in other organisms) and one copy each of subunits a, b, d, h (F6) and OSCP. Subunits b, d, F6 (h) and OSCP form the peripheral stalk which lies to one side of the complex. A number of additional subunits (e, f, g, i/j, k and A6L) are associated with F0, although their precise locations within the complex remain uncertain (see discussion below). The F0 and F1 sectors of the enzyme, and the two stalks connecting them, are clearly visible in electron cryomicroscopy images of mtATPase (Rubinstein et al., 2003).

2.2. Rotary catalysis Synthesis of ATP by F1F0-ATPase is achieved by coupling the activities of two rotary motors; one in F0, for which a rotational mechanism was first proposed by Cox et al. (1984), and the other in F1 (Boyer and Kohlbrenner, 1981). The presence of a proton motive force drives protons through a channel in F0 at the interface between subunit a and the subunit c ring. In the case of the mitochondrial enzyme, protons pass from the intermembrane space into the matrix. This releases energy which causes rotation of the ring (relative to subunit a), along with subunits g, d, and e, to which it is attached. In turn, rotation of subunit g within the F1 a3b3 hexamer provides energy for ATP synthesis at the catalytic sites (located in each of the three b subunits, at the interface with an adjacent a subunit). The rotary mechanism of F1-ATPase was proved in remarkable singlemolecule experiments carried out by Noji et al. (1997). The a3b3 hexamer of bacterial F1 was immobilised on a flat surface, and ATP-dependent rotation of a fluorescently labelled actin filament attached to the g subunit was directly observed under the fluorescence microscope. A similar technique was used to show that the hydrolysis of one molecule of ATP causes a

b a, b, g, d, e, Walker et al., 1985; Su6, A6L, Fearnley and Walker, 1986; Su9, Sebald and Hoppe, 1981; b, d, Walker et al., 1987b; OSCP, F6, INH, Walker et al., 1987a; e, Walker et al., 1991; f,g, Collinson et al., 1994a. c Compilation of data for both yeast and bovine systems presented in Arnold et al., 1998; Fronzes et al., 2003; Gregory and Hess, 1981; Hekman et al., 1991; Muraguchi et al., 1990; Okada et al., 1986; Paumard et al., 2000; Stephens et al., 2003; Stutterheim et al., 1981; Todd et al., 1980; and Walker et al., 1985. A question mark indicates subunits for which no reliable stoichiometric data are available. d Arakaki et al., 2001.

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rotation of 120
(Yasuda et al., 2001), as would be expected from the existence of three catalytic sites. Binding of ATP causes a rapid (