학술논문
ADGRL4/ELTD1 is a highly conserved angiogenesis-associated orphan adhesion GPCR that emerged with the first vertebrates and comprises 3 evolutionary variants
EGF, latrophilin and seven transmembrane domain-containing protein 1
Adhesion G Protein-Coupled Receptor L4
G-protein-coupled receptors
EGF, latrophilin and seven transmembrane domain-containing protein 1
Adhesion G Protein-Coupled Receptor L4
G-protein-coupled receptors
Document Type
Report
Source
BMC Evolutionary Biology. July 12, 2019, Vol. 19 Issue 1
Subject
Language
English
ISSN
1471-2148
Abstract
Author(s): David M. Favara[sup.1,2] , Alison H. Banham[sup.3] and Adrian L. Harris[sup.2] Background Discovered in 2001 [1], ELTD1/ADGRL4 is an orphan member of the G protein-coupled receptor (GPCR) superfamily, belonging [...]
Background Our laboratory identified ADGRL4/ELTD1, an orphan GPCR belonging to the adhesion GPCR (aGPCR) family, as a novel regulator of angiogenesis and a potential anti-cancer therapeutic target. Little is known about how ADGRL4/ELTD1 (and aGPCRs in general) function, a problem compounded by a lack of known ligands or means of activation. With this in mind, we turned to computational evolutionary biology with the aim of better understanding ADGRL4/ELTD1. Results We identified ADGRL4/ELTD1 as a highly conserved early angiogenic gene which emerged in the first true vertebrates (bony fish) approximately 435 million years ago (mya), evolving alongside key angiogenic genes VEGFR2 and DLL4. We identified 3 evolutionary ADGRL4/ELTD1 variants based on EGF domain deletions with variant 2 first emerging 101 mya (95% CI 96-105) in Afrotheria and 82 mya (95% CI 76-89) in Primates. Additionally, conservation mapping across all orthologues reveals highest level conservation in EGF Ca binding domain 1, suggesting that this motif plays an essential role, as well as specific regions of the GAIN domain, GPS motif and 7TM domain, suggesting possible activation mechanisms and ligand binding positions. Additionally, we found that ADGRL4/ELTD1 (a member aGPCR family 1) is possibly ancestral to members of aGPCR family 2. Conclusion This work establishes ADGRL4/ELTD1's evolution, sheds light on its possible activation and ligand binding zones, and establishes the first temporal references for the emergence of ADGRL4/ELTD1 variants during vertebrate evolution. Our approach is applicable to the greater aGPCR family and opens up new avenues for future experimental work. Keywords: ADGRL4, ELTD1, Adhesion GPCR evolution
Background Our laboratory identified ADGRL4/ELTD1, an orphan GPCR belonging to the adhesion GPCR (aGPCR) family, as a novel regulator of angiogenesis and a potential anti-cancer therapeutic target. Little is known about how ADGRL4/ELTD1 (and aGPCRs in general) function, a problem compounded by a lack of known ligands or means of activation. With this in mind, we turned to computational evolutionary biology with the aim of better understanding ADGRL4/ELTD1. Results We identified ADGRL4/ELTD1 as a highly conserved early angiogenic gene which emerged in the first true vertebrates (bony fish) approximately 435 million years ago (mya), evolving alongside key angiogenic genes VEGFR2 and DLL4. We identified 3 evolutionary ADGRL4/ELTD1 variants based on EGF domain deletions with variant 2 first emerging 101 mya (95% CI 96-105) in Afrotheria and 82 mya (95% CI 76-89) in Primates. Additionally, conservation mapping across all orthologues reveals highest level conservation in EGF Ca binding domain 1, suggesting that this motif plays an essential role, as well as specific regions of the GAIN domain, GPS motif and 7TM domain, suggesting possible activation mechanisms and ligand binding positions. Additionally, we found that ADGRL4/ELTD1 (a member aGPCR family 1) is possibly ancestral to members of aGPCR family 2. Conclusion This work establishes ADGRL4/ELTD1's evolution, sheds light on its possible activation and ligand binding zones, and establishes the first temporal references for the emergence of ADGRL4/ELTD1 variants during vertebrate evolution. Our approach is applicable to the greater aGPCR family and opens up new avenues for future experimental work. Keywords: ADGRL4, ELTD1, Adhesion GPCR evolution