Molecular evolution of CRH and CRHR subfamily before the evolutionary origin of vertebrate.

Corticotropin-releasing hormone (CRH) is well-cited for its important role in governing the stress responses via neuroendocrine system in vertebrates. After the identification of homologs of CRH receptor (CRHR) in both deuterostome and arthropod lineages, it was suggested that the ancestral homolog of CRH-CRHR molecular system is present in the bilaterian. However, homolog sequences from arthropods differ considerably from vertebrate CRH-like peptide sequences. Due to the significant difference between the biological system, as well as the gene regulatory network, of protostome and that of vertebrate, physiological studies on the protostomes may not provide important insight into the evolutionary history of vertebrate CRH system, while tunicate and amphioxus, two close relatives to vertebrate, which have diverged before two rounds of whole genome duplication (2WGDs) do. Given the identification of amphioxus CRH-like peptide by our group, this review aims to reexamine the current hypotheses on the evolution of CRH subfamily. It is generally accepted that paralogs of CRH and CRHR have been produced through 2WGDs, which occurred during the early vertebrate evolution. The identification of a single crh-like gene in amphioxi and tunicates by in silico search and the presence of two paralogons with a total of 5 crh-like genes in gnathostomes has shown that an additional duplication event might have happened to the ancestral crh-like gene before 2WGDs. On the other hand, the evolution of crhr gene subfamily appears to be mainly influenced by 2WGDs and only two receptor genes have been retained in the genomes of jawed vertebrates.

Correction: Structure-Activity Relationship Studies of N- and C-Terminally Modified Secretin Analogs for the Human Secretin Receptor.

[This corrects the article DOI: 10.1371/journal.pone.0149359.].

Structure-Activity Relationship Studies of N- and C-Terminally Modified Secretin Analogs for the Human Secretin Receptor.

The pleiotropic role of human secretin (hSCT) validates its potential use as a therapeutic agent. Nevertheless, the structure of secretin in complex with its receptor is necessary to develop a suitable therapeutic agent. Therefore, in an effort to design a three-dimensional virtual homology model and identify a peptide agonist and/or antagonist for the human secretin receptor (hSR), the significance of the primary sequence of secretin peptides in allosteric binding and activation was elucidated using virtual docking, FRET competitive binding and assessment of the cAMP response. Secretin analogs containing various N- or C-terminal modifications were prepared based on previous findings of the role of these domains in receptor binding and activation. These analogs exhibited very low or no binding affinity in a virtual model, and were found to neither exhibit in vitro binding nor agonistic or antagonistic properties. A parallel analysis of the analogs in the virtual model and in vitro studies revealed instability of these peptide analogs to bind and activate the receptor.