Biology Reference
In-Depth Information
9.1 Introduction
9.1.1 F 1 F 0 ATP Synthase Structure and Mechanism
F 1 F 0 ATP synthase is a multi-subunit enzyme complex that is best known for its
ATP-synthesizing role as Complex V in the electron transport chain in mitochondria.
The F 0 portion of the protein acts as a proton channel situated within the inner mito-
chondrial membrane. The soluble F 1 portion is composed of five subunits (
α 3 β 3 γδε
)
α
β
and oriented toward the mitochondrial matrix. The
subunits are arranged in
an alternating hexameric pattern that is attached to F 0 by a central and peripheral
stalk. The
and
γ
and
ε
subunits form the rotating central stalk that extends into the mid-
dle of the
subunit combines with the b subunit of F 0 to form
the static peripheral stalk (Fig. 9.1a) [8, 10].
ATP synthase couples the energy generated by protons translocating down their
gradient through F 0 with the formation of a high-energy phosphoanhydride bond.
The movement of protons through the channel induces an internal rotation of a ring
of c subunits in F 0 , leading to rotation of the attached
α 3 β 3 ring, while the
δ
subunit in the central stalk
of F 1 . This in turn triggers a series of conformational changes of the catalytic
γ
β
subunits, which synthesize ATP from adenosine diphosphate (ADP) and inorganic
phosphate (P i ). This “binding change mechanism” proposed by Paul Boyer drives
the generation of ATP by each of the three
sub-
units can also catalyze ATP hydrolysis, which engenders conformational changes
that drive rotation of the central stalk of F 1 in the opposite direction. Rotation in
this direction is associated with proton translocation against the proton gradient,
utilizing the energy provided by hydrolyzing ATP to ADP and P i [9].
β
subunits in succession. The
β
9.1.2 Cell Surface F 1 F 0 ATP Synthase
In 1994 Das et al. discovered the presence of the
subunit of ATP synthase on the
cell surface of three human tumor cell lines [16]. ATP synthase had previously been
known to exist in the plasma membrane of bacteria, inner mitochondrial membrane,
and the thylakoid membrane of chloroplasts; however, this report marked the first
identification of a component of ATP synthase in the cell membrane of a eukary-
otic cell (Fig. 9.1b). Five years later, our laboratory identified cell surface F 1 F 0 ATP
synthase as a receptor for angiostatin on human endothelial cells [26]. Confocal
microscopy of nonpermeabilized endothelial cells demonstrated colocalization of
the
β
subunits, distributed in a punctate pattern on the cell surface, consistent
with arrangement in caveolae (Fig. 9.2) [25]. These findings were initially contro-
versial due to the long-held belief that this protein existed only as an intracellular
enzyme in eukaryotes; however, ATP synthase has since then been detected on the
surface of several other normal cell types, including hepatocytes, adipocytes, and
keratinocytes, as well as additional cancer cell lines. In hepatocytes, it functions as
a receptor for apolipoprotein A-I, which upon binding stimulates ATP hydrolysis
α
and
β
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