Nobel Centennial Symposia
"Frontiers of Molecular Science"

December 4-7, 2001
Friiberghs Manor, Örsundsbro and Stockholm University

The Rotary Mechanism of ATP Synthase

by John E. Walker
Medical Research Council, Dunn Human Nutrition Unit, Hills Road, Cambridge, CB2 2XY, UK

The ATP synthase from mitochondria, bacteria and chloroplasts is a complex multisubunit enzyme that works by a rotary mechanism. It has two major domains, one known as F_o, is buried in the membrane, and the other a globular domain known as F₁ sits outside the membrane and is connected to F_o by a central stalk. The proton motive force across the membrane provides the energy for rotation which is generated in F_o by a rotary motor consisting of a ring of 11-14 c-subunits (depending on the species [1]), turning against a single subunit a. The central stalk (made of subunits d, e, and g) is intimately associated with the c-ring [2,3] and they rotate together as an ensemble. The central stalk penetrates through the F₁ domain and is surrounded by a spherical assembly of 3a and 3b subunits arranged in alternation around the axis of the central stalk [4]. Catalytic sites (there are three) lie mainly in b-subunits at interfaces with a-subunits. The rotation deforms these sites and takes them through states that are ready (the empty state) to move to a substrate accepting state, which then closes to entrap ADP and phosphate (the tight state) allowing ATP to form (the loose state) and then being released as the empty state reforms. These three states (empty, tight and loose) have been defined by structural analysis and more recently by forming transition state analogue complexes intermediate states have been defined structurally [5]. In other words six states in the catalytic pathway have now been defined at high resolution.

Another important aspect of ATP synthase is how is it regulated by its natural inhibitor IF₁. The free protein has two well defined oligomeric states, an active dimer and an inactive dimer of dimers [6-8]. Their structure has also been determined [9] and the current issue is how does the IF₁ inhibit ATP synthase? These and other aspects of regulation of ATP synthase will be discussed in the lecture.

 

References

1. D Stock, C Gibbons, I Arechaga, A G W Leslie and J E Walker (2000). Current. Opinion Struct. Biol. 10, 672-679

2. D Stock, A G W Leslie and J E Walker (1999). Science 286, 1700-1705.

3. C Gibbons, M G Montgomery, A G W Leslie and J E Walker (2000). Nature Struct. Biol. 7, 1055-1061.

4. J P Abrahams, A G W Leslie, R Lutter and J E Walker (1994). Nature 370, 621-628.

5. I R Menz, J E Walker and A G W Leslie (2001). Cell, In the press.

6. E Cabezon, P J G Butler, M J Runswick and J E Walker (2000). J. Biol. Chem. 275, 25460-25464.

7. E Cabezon, I Arechaga, P J G Butler and J E Walker (2000). J. Biol. Chem. 275, 28353-28355.

8 D-J Gordon Smith, R J Carbajo, J-C Yang, H Videler, M J Runswick, J E Walker and D Neuhaus (2001) J. Mol. Biol. 308, 325-329.

9. E Cabezon, M J Runswick, A G W Leslie and J E Walker (2001) EMBO.J. In the press.