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Identifying the binding mechanism of LEAP 2 to receptor GHSR 1a
Author(s) -
Wang JiaHui,
Li HaoZheng,
Shao XiaoXia,
Nie WeiHan,
Liu YaLi,
Xu ZengGuang,
Guo ZhanYun
Publication year - 2019
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.14763
Subject(s) - ghrelin , agonist , receptor , growth hormone secretagogue receptor , endocrinology , competitive antagonist , medicine , chemistry , antagonist , peptide , endogenous agonist , secretagogue , biology , biochemistry , dopamine receptor d1
Liver‐expressed antimicrobial peptide 2 ( LEAP 2) is a highly conserved secretory peptide first isolated in 2003. However, its exact biological functions remained elusive until a recent study identified it as an endogenous antagonist for the growth hormone secretagogue receptor ( GHSR 1a), a G protein‐coupled receptor for which the gastric peptide ghrelin is the endogenous agonist. By tuning the ghrelin– GHSR 1a system, LEAP 2 has an important function in energy metabolism. In the present study, we first demonstrated that LEAP 2 and ghrelin actually bound to GHSR 1a in a competitive manner, rather than in a non‐competitive manner as previously reported, by binding assays and activation assays. Subsequently, we demonstrated that the antagonistic function of LEAP 2 was drastically affected by the manner of its addition. LEAP 2 primarily affected the maximal activation effect when added before ghrelin, whereas it primarily affected half‐maximal effective concentration when added at the same time as ghrelin. Thus, LEAP 2 behaved as a competitive antagonist if added at the same time as the agonist and a non‐competitive antagonist if added before the agonist. This unusual property of LEAP 2 might be caused by its slow dissociation from receptor GHSR 1a. We also found that the N‐terminal fragment of LEAP 2 was important for receptor binding. Our present study revealed an antagonistic mechanism for LEAP 2, and will facilitate the design of novel antagonists for receptor GHSR 1a in future studies.