Discussion
Here, we describe for the first time the concept of “coral
pharmacology” where we aim to develop pharmacological approaches
towards potentially treating corals who have been harmed by human
pollution. Using the insulin-IR system as a proof of concept, we
developed a pipeline for establishing the functional similarities
between human and coral membrane receptor signaling systems. Insulin is
responsible for regulation of nutrient concentration in human, and will
likely carry out a similar function in corals. This is the premise that
we investigated in depth in this paper.
Structural biology has made major strides in understanding the
mechanisms of insulin binding to the IR, the conformational changes
induced and subsequent modulation of downstream signal transduction. We
have now investigated the evolution of the insulin signaling system
through sequence and structure analysis. Evolutionary early species such
as cnidarian animal hosts in corals use the system despite their simple
organization. Transcriptomic analysis had revealed that insulin
signaling plays a major role in the establishment of symbiosis between
cnidarian host animals and algal symbionts
(Yuyama et al., 2018). Given
that one of the major benefits of symbiosis is the delivery of sugars
obtained through photosynthesis of the algae to the host, we can expect
that the role of insulin signaling is analogous in corals to that in
humans, despite their evolutionary distance. It is tempting to speculate
that under high light conditions, when the algae synthetize excess
sugars, that the cnidarian host may experience insulin resistance, a
hypothesis that remains to be validated experimentally.
We found that there is strong conservation at the structural level at
the functionally important ligand interfaces, despite the large
divergence in sequence, supporting that the insulin and IR homologues
function similarly to their human counterparts. To further find support
for this hypothesis, we extracted from the literature all the proteins
involved in the signaling pathways activated by binding of insulin to
the IR. In addition, we also extracted proteins from related pathways,
glucagon and somatostatin, which are known to down-regulate insulin
signaling. Interestingly, these two hormones are missing homologues in
corals. It is tempting to conclude that while Corals can regulate
nutrient uptake/release via insulin signaling, regulation of insulin
signaling by other pathways may not function. We speculate that perhaps
these ligands may be provided by the microbiome. Perhaps it is bacteria
or algae which generate ligands for negative regulation of insulin
signaling. This would make sense since this may save nutrients
extracellularly for their consumption rather than allowing uptake into
the coral cells.
The finding of conservation of the insulin system across 700 millions
years linking human and coral proteins is not surprising and add a new
system to a growing list of organisms: Insulin-like molecules have been
identified in prokaryotes, microbial eukaryotes, insects, invertebrates,
plants (LeRoith et al.,
1981) (Le Roith et al.,
1980) (Baig and Khaleeq,
2020). Antibodies raised against human insulin recognizes insulin like
material from unicellular eukaryotes such as Tetrahymena pyriformis, a
ciliated protozoan, and Neurospora crassa
(Kole et al., 1991;
Muthukumar and Lenard, 1991) and Aspergillus fumigatus, both fungi, and
even prokaryotes (LeRoith et
al., 1981). The fact that both prokaryotes and eukaryotes synthesize
insulin suggests that it may play a role in co-evolution, potentially
supporting our above hypothesis of the insulin system playing a role in
the communication across the coral microbiome.
The conservation at the sequence level is mirrored by conservation at
the functional level
(Abou-Sabe’ and Reilly,
1978) (Le Roith et al.,
1980). For example, effects of mammalian insulin on E. coli have been
described. Similarly, insulin shows metabolic effects on Neurospora
crassa cells such as enhanced glucose metabolism, enhanced growth,
improved viability, accumulation of intracellular sodium. The
insulin-like preparations from more primitive organisms have effects on
rat cells. It has also been shown that these functional effects are
likely achieved through a phosphorylation cascade as shown by the
enhanced phosphorylation of specific proteins on serine/threonine and
tyrosine residues (Kole et
al., 1991).
Most recently, an insulin-IR pair has been described in detail for
Acanthamoeba castellanii, an early mitochondria unicellular eukaryotic
organism (Baig and Khaleeq,
2020). Not only did they show typical mammalian insulin-induced effects
on Acanthamoeba cells, but they also investigated the anti-diabeteic
drug, metformin, and conducted homology modeling of the putative
Acanthamoeba insulin-IR pair. This study strongly supports the notion of
a high degree of conservation of the insulin-IR pair across billions of
years of evolution, and pioneers the use of a human antidiabetic drug
(metformin) in the context of a primitive organism.
The findings described here for the insulin system may extrapolate also
to other hormones. Insulin is not the only mammalian hormone that is
found in many more primitive organisms. Prokaryotic and eukaryotic
microbes contain calcitonin, corticotropin, gonadotropin, relaxin,
somatostatin, thymosin and thyrotropin
(Kole et al., 1991;
Muthukumar and Lenard, 1991).
While the focus of this paper has been on a single ligand-receptor
complex and its downstream signaling network, extending our detailed
understanding from the well studied human organism to the new coral
system (pdam, specifically), we would like to point out that such
extensions from model to non-model organisms is general. The explosion
in sequence data obtainable for non-model organisms makes approaches
described here very desirable, as we can extrapolate to function from
the sequence data via structural and systems biology.
Table 1 . Matching residues in human insulin receptor with
corresponding residues in coral insulin receptor