Biology Reference
In-Depth Information
data on the extracellular domains of EpoR, known as the EPO-binding protein
(EBP), have indicated that EpoR can form a dimmer in the absence of EPO (Livnah
et al. 1999), consistent with PFH, that is, Process
7.14
.
The pre-fit hypothesis is supported by recent experimental results reviewed in
Kurakin (2009). In particular the following statement by Kurakin accurately
captures the essences of the pre-fit mechanism of ligand-protein interactions and
'info-statistical mechanics discussed in Sect. 4.9:
. . . The latest studies addressing the structure and dynamics of various enzymes suggest that
the walk of a protein structure through its conformational landscape is actually not random,
but proceeds along statistically preferred routes that, strikingly enough, happen to corre-
spond to the conformational changes observed during actual enzymic catalysis ...Inother
words, a substrate-free enzyme prefers to sample the sequence of coupled conformational
transitions that correspond to actual changes in its structure when the eynzyme peforms its
function.
It may be stated that Kurakin's review article, along with the other experimental
evidence discussed in this topic, establishes the validity of the pre-fit hypothesis
that was formulated a quarter of a century ago based on the generalized Franck-
Condon principle (Ji 1974a, b).
7.1.4 The Franck-Condon Mechanism of Ligand-Membrane
Channel Interactions
In passive transport, the ion
selectivity
is imparted by the ion channel protein, but the
direction of ion
movement
is determined by the Gibbs free energy change
accompanying the ion movement. In active transport, however, the transporting
proteins can provide both the selectivity to ions (or other ligands) and the Gibbs free
energy needed for the ligand movement across the membrane against the concentra-
tion gradient of transported ions. The pre-fit hypothesis mandates that biopolymers
undergo conformational changes before a ligand can bind to its receptor as indicated
above. This hypothesis was formulated on the basis of the Principle of Slow and Fast
Processes (PSFP), or the
generalized Franck-Condon principle
(GFCP), according
to which the slower of any two coupled processes must precede the faster one in
order for the slow and fast processes to be coupled (Sect.
2.2.3
).
A simplified representation of the mechanism of passive ion movement across
the cell membrane based on GFCP is shown in Fig.
7.2
. The ion channel (see the
dotted square) is postulated to have two ligand-binding sites, which generate three
channels
(or gates) across the biological membrane (to be denoted as upper, middle,
and lower gates). Each gate has two conformational states -
open
and
closed
. The
ligand binds to its upper binding site only when the upper gate happens to be in the
open state (see
1
,
2
&
3
). As the upper gate closes, the middle gate opens (see 3 & 4),
all as a part of thermal fluctuations of the gate proteins. Notice that States 5 through
8 are symmetric with (or mirror images of) States 1 through 4, thereby implementing
the same mechanisms entailed by GFCP.
