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