Biology Reference
In-Depth Information
As for the shortest communication pathways, rhodopsin's fold is such that, in both
functional states, the most likely pathways express a vertical communication between
the two poles of the transmembrane helix bundle, in line with the fact that nature made
GPCRs competent to transfer signals from the outside to the inside of the cell (
Fig. 3.5
).
Consistent with the more dense retinal-involving network in the dark state, the number
of pathways that pass through retinal is higher in the dark state (i.e., 73%,
Table 3.1
)
compared to MII (i.e., 59%,
Table 3.1
). On average, paths characterizing the inactive
state are shorter and more stiff and tend to involve a major number of hubs than those
characterizing the MII state (
Table 3.1
and
Fig. 3.6
). Striking different communication
modes are expressed by the meta paths of the two functionally different states
(
Fig. 3.5
). In the dark state, the gross of the communication involves E2, retinal,
H6, and H7. The most recurrent nodes in the helices and their respective links in
the meta path of such state sketch the following pathway: RET-W6.48-F6.44-
WAT-N7.49-M6.40-M6.46-Y7.53 (
Fig. 3.5
). In contrast, the meta path characterizing
the MII state describes a vertical communication essentially involving retinal, H6, H5,
and the C-terms of H3 and H8 (
Fig. 3.5
). In this case, the most recurrent nodes in the
helices and their respective links sketch the following pathway: F5.43-RET-W6.48-
F6.44-WAT-Y7.53-M6.40-Y5.58-R3.50. Remarkably, in both states, the W6.48-
F6.44 aromatic pair in H6 mediates the communication between chromophore-binding
site and cytosolic regions. Meta path comparisons highlight a shift of the communica-
tion towards the intracellular regions and a reduction in the contribution by the extra-
cellular portions on going from the dark to the MII state. In the latter, the cytosolic end
of the pathways involves Y5.58 and the E/DRY arginine. These data suggest that
whereas in the inactive states the structural communication serves essentially to ensure
structural stability, in the active form, it serves to maintain a binding site for the G
protein in the cytosolic regions of the receptor.
Collectively, PSN-ENM applied to the dark and MII states of rhodopsin reveals
the structure networks as expression of enhanced stability of the inactive state com-
pared to the active one, highlighting also the receptor portions responsible for such
stability differences, which strongly the retinal-binding site. Finally, the structural
communication appears to hold different functional competences in the inactive
and active states.
SUMMARY
PSN analysis is a powerful tool to unveil the structure communication in biomolec-
ular systems and hence suitable for GPCRs that are designed to receive and transfers
inputs from the outside to the inside of the cell. Applications of two different variants
of the PSN approach, that is, PSN-MD and PSN-ENM, served to investigate the
roles of misfolding or activating mutations, ligand binding, and receptor dimeriza-
tion on the structural communication features of a number of GPCRs in different
functional forms. Comparison of network features is a powerful tool to decipher
the structural signatures of functionally different states in different sets of homolo-
gous proteins at varying degree of similarity.