Positive selection in cathelicidin host defense peptides: adaptation to exogenous pathogens or endogenous receptors?

Abstract

The cause of adaptive protein evolution includes internal (for example, co-evolution of ligand-receptor pairs) and external (for example, adaptation to different ecological niches) mechanisms. Host defense peptides (HDPs) are a class of vertebrate-specific cationic antimicrobial peptides evolving under positive selection. Besides their antibiotic activity, HDPs also exert an effect on multiple host immune cells, thus providing an ideal model to study selective agents driving their evolution. On the basis of a combination of computational and experimental approaches, we studied the evolution of LL-37-type HDPs in mammals, the mature peptide of cathelicidin CAP18 (herein termed CAP18-MP) and investigated the driving force behind the evolution. Using codon-substitution maximum likelihood models, we analyzed CAP18-MPs in 40 species belonging to nine mammalian Orders and identified four positively selected sites (PSSs) that all are located on two terminal unordered regions of CAP18-MPs. Grafting the two positively selected regions of human or whale CAP18-MP to the α-helical scaffold of a rabbit homolog (substituting its corresponding parts) led to no alterations in antibacterial activity, spectrum and action mode. Likewise, further deletion of the two terminal regions did not alter its functional features. Evolutionary conservation analysis of mammalian FPR2, a receptor known to interact with the C-terminal positively selected region of LL-37, revealed high evolutionary variability in its ligand-binding extracellular loop domains, matching sequence diversity of the unordered regions in CAP18-MPs. This is the first report describing that the signature of positive selection of cathelicidins is not associated with their direct bactericidal activity, but rather with the evolutionary variability of their endogenous receptors.

Cathelicidin Host Defense Peptides and Inflammatory Signaling: Striking a Balance

“…However, as mentioned above, the antimicrobial potency of most HDPs remains rather modest in host-like environments. A recent study of mammalian homologs of LL-37 proposed that the driving force behind the evolution of cathelicidins might be their interaction with host receptors ( Zhu and Gao, 2017 ), which is consistent with the concept that immune response elements are one of the most highly evolving groups of proteins across mammalian species ( Hahn et al, 2007 ; Kosiol et al, 2008 ).…”

“…An earlier study suggested that the disordered C-terminus of LL-37 interacts with the N-formyl peptide receptor-like (FPR) family of proteins ( Singh et al, 2014 ), as part of the process to mediate chemotaxis. Sequence analysis of the human FPR2 receptor indicated high variability in the ligand-binding extracellular loop domain, while the C-terminus of mammalian LL-37 homologs was disordered; thus statistical analysis revealed a possible co-evolution of this peptide as a cognate binding partner for FPR2 was proposed ( Zhu and Gao, 2017 ). Furthermore, the elimination of the disordered N- and C-terminal regions in the rabbit LL-37-homolog (CAP18-FV) or their replacement with disordered regions from the dolphin (ttLL-37) or human homologs had no impact on the anti-bacterial activity.…”

Adaptively evolved human oral actinomyces‐sourced defensins show therapeutic potential

“…Of all these properties relevant to therapeutic efficacy, AMSIN is superior to eukaryotic AMPs (e.g., human LL‐37 and defensins). The latter often exhibits potent mammalian cytotoxicity with stronger immunomodulatory activity and serum instability and inactivation (Panyutich et al , 1995 ; Johansson et al , 1998 ; Scott et al , 2002 ; Hara et al , 2008 ; Zhu & Gao, 2017 ; Kudryashova et al , 2021 ). From an evolutionary viewpoint, natural selection on mammalian LL‐37 has been proposed to be driven by their endogenous receptors mediating the immunomodulatory functions rather than by exogenous pathogens (Zhu & Gao, 2017 ).…”

受体的多样性驱动蛇毒的进化

“…Excess nonsynonymous substitutions compared with synonymous substitutions (ω= d N / d S >1) is an important sign of positive selection at the molecular level ( Yang, 1998 ; Zhu & Gao, 2016 ). To perform such analysis, we compared two pairs of site models (M1a (neutral)/M2a (selection) and M7 (beta)/M8 (beta & )) to measure the selective pressure of the receptors to which the long α-NTXs bind (α1, α7, α9 and α10 subunits from nAChRs).…”