Chemokine Receptor N-Terminus Charge Dictates Reliance on Post-Translational Modifications for Effective Ligand Capture and Following Boosting by Defense Peptides. Int J Mol Sci 2024 Oct 09;25(19)
Date
10/16/2024Pubmed ID
39409188Pubmed Central ID
PMC11477141DOI
10.3390/ijms251910854Scopus ID
2-s2.0-85206465330 (requires institutional sign-in at Scopus site) 2 CitationsAbstract
The chemokine receptors CCR1 and CCR5 display overlapping expression patterns and ligand dependency. Here we find that ligand activation of CCR5, not CCR1, is dependent on N-terminal receptor O-glycosylation. Release from O-glycosylation dependency is obtained by increasing CCR5 N-terminus acidity to the level of CCR1. Ligand activation of CCR5, not CCR1, drastically improves in the absence of glycosaminoglycans (GAGs). Ligand activity at both CCR1 and CCR5 is boosted by positively charged/basic peptides shown to interact with acidic chemokine receptor N-termini. We propose that receptors with an inherent low N-terminus acidity rely on post-translational modifications (PTMs) to efficiently compete with acidic entities in the local environment for ligand capture. Although crucial for initial ligand binding, strong electrostatic interactions between the ligand and the receptor N-terminus may counteract following insertion of the ligand into the receptor binding pocket and activation, a process that seems to be aided in the presence of basic peptides. Basic peptides bind to the naked CCR1 N-terminus, not the CCR5 N-terminus, explaining the loss of boosting of ligand-induced signaling via CCR5 in cells incapable of glycosylation.
Author List
Xu T, Schou AS, Lackman JJ, Barrio-Calvo M, Verhallen L, Goth CK, Jensen BAH, Veldkamp CT, Volkman BF, Peterson FC, Hjortø GMAuthor
Brian F. Volkman PhD Professor in the Biochemistry department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsGlycosaminoglycans
Glycosylation
Humans
Ligands
Peptides
Protein Binding
Protein Processing, Post-Translational
Receptors, CCR1
Receptors, CCR5
