Abstract
Tumor cell surface aminopeptidase N (APN or CD13) has two puzzling functions unrelated to its enzymatic activity: mediating tumor cell motility and serving as a receptor for tumor-homing peptides (peptides that bring anti-cancer drugs to tumor cells). To investigate APN-based tumor-homing therapy, we determined the crystal structure of APN complexed with a tumor-homing peptide containing a representative Asn-Gly-Arg (NGR) motif. The tumor-homing peptide binds to the APN enzymatic active site, but it resists APN degradation due to a distorted scissile peptide bond. To explore APN-based tumor cell motility, we examined the interactions between APN and extracellular matrix (ECM) proteins. APN binds to, but does not degrade, NGR motifs in ECM proteins that share similar conformations with the NGR motif in the APN-bound tumor-homing peptide. Therefore, APN-based tumor cell motility and tumor-homing therapy rely on a unified mechanism in which both functions are driven by the specific and stable interactions between APN and the NGR motifs in ECM proteins and tumor-homing peptides. This study further implicates APN as an integrin-like molecule that functions broadly in cell motility and adhesion by interacting with its signature NGR motifs in the extracellular environment.
Highlights
Aminopeptidase N (APN) mediates tumor cell motility and is a receptor for tumor-homing peptides containing NGR motifs
CNGRCG was chosen for the study because it is the most commonly used tumor-homing NGR peptide and targets tumor cells more effectively than other NGR peptides such as GNGRG [6, 44]. porcine APN (pAPN) was chosen for this study because it was previously crystallized in a closed and catalytically active conformation under physiologically relevant pH, and the crystals diffracted to high resolution (ϳ2.0 Å) [9]
Our study has identified a unified mechanism for APN-based tumor cell motility and tumor-homing therapy where APN carries out these functions by interacting with the NGR motif in extracellular matrix (ECM) proteins and in tumor-homing peptides, respectively (Fig. 8)
Summary
Aminopeptidase N (APN) mediates tumor cell motility and is a receptor for tumor-homing peptides containing NGR motifs. Tumor cell surface APN mediates tumor cell motility and serves as a receptor for tumor-homing peptides that guide anti-cancer drugs to tumor cells; these functions appear to be unrelated to each other or to APN’s enzymatic activity [3,4,5,6,7,8] It is puzzling how APN, a zinc-dependent aminopeptidase in essence, can function as a cell motility molecule and as a tumor-homing receptor. In addition to binding peptides, pAPN binds the exposed N terminus of proteins by undergoing a closed-to-open conformational change, which opens up its active site cavity These results have elucidated the enzymatic activity of APN, but the puzzling roles of APN in tumor cell motility and tumor-homing therapy are still unclear. Our study establishes APN as an integrin-like cell motility and adhesion molecule that should be investigated in depth and exploited therapeutically
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