Corticotropin-Releasing Factor: An Ancient Peptide Family Related to the Secretin Peptide Superfamily.

Ola M Michalec,Nathan R Lovejoy,David A Lovejoy,Belinda S W Chang

doi:10.3389/fendo.2020.00529

Abstract

Corticotropin-releasing factor (CRF) is the hypothalamic releasing peptide that regulates the hypothalamic-pituitary-adrenal/inter-renal (HPA/I) axis in vertebrates. Over the last 25 years, there has been considerable discussion on its paralogs genes, urotensin-I/urocortin-1, and urocortins-2 and-3 and their subsequent role in the vertebrate stress response. Phylogenetically, the CRF family of peptides also belong to the diverse assemblage of Secretin- and Calcitonin-based peptides as evidenced by comparative-based studies of both their ligand and G-protein-coupled receptor (GPCR) structures. Despite this, the common origin of this large assemblage of peptides has not been ascertained. An unusual peptide, teneurin-C-terminal associated peptide (TCAP), reported in 2004, comprises the distal extracellular tip of the teneurin transmembrane proteins. Further studies indicated that this teneurin region binds to the latrophilin family of GPCRs. Initially thought to be a member of the Secretin GPCR family, evidence indicates that the latrophilins are a member of the Adhesion family of GPCRs and are related to the common ancestor of both Adhesion and Secretin GPCR families. In this study, we posit that TCAP may be a distantly related ancestor of the CRF-Calcitonin-Secretin peptide family and evolved near the base of metazoan phylogeny.

Highlights

Corticotropin-releasing factor (CRF) is the critical hypothalamic releasing factor that regulates the hypothalamus-pituitary-adrenal/inter-renal (HPA/1) axis in vertebrates, yet after some 40 years after its discovery, numerous questions still exist regarding when, why, and how this peptide evolved
Evolutionary relationships among the receptors of these ligands demonstrate that Secretin G-protein-coupled receptor (GPCR) derived from Adhesion GPCRs [19] and as terminal associated peptide (TCAP)-1 binds to LPHN, an Adhesion GPCR with a hormonebinding domain (HBD) characteristic of Secretin GPCRs [17]
We suggest that if the ligands for these receptors underwent a similar course in evolution, the TCAP family may be a putative progenitor to the Secretin superfamily

Summary

Introduction

Corticotropin-releasing factor (CRF) is the critical hypothalamic releasing factor that regulates the hypothalamus-pituitary-adrenal/inter-renal (HPA/1) axis in vertebrates, yet after some 40 years after its discovery, numerous questions still exist regarding when, why, and how this peptide evolved. We hypothesize that due to the high level of primary structure similarity among CRF paralogs and related peptide lineages (e.g., calcitonin, secretin) there was likely an ancestor peptide common to this cluster. We further suggest that the “teneurin C-terminal associated peptides” (TCAP) represent an extant candidate lineage related to the hypothetical common ancestor. The discovery of CRF in the early 1980s [1] occurred about the same time as the discovery of other peptides of similar structure [sauvagine [2]; urotensin-I [3]]. Vale and his laboratory characterized a mammalian version of sauvagine/urotensin-I in rat brain that they termed, urocortin [4]. In 2001, the structures of two novel related peptides were reported by the Vale laboratory who named the peptides, urocortin 2

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Discussion

Conclusion