The N-terminal domain of APJ, a CNS-based coreceptor for HIV-1, is essential for its receptor function and coreceptor activity.
The human APJ, a G protein-coupled seven-transmembrane receptor, has been found to be dramatically expressed in the human central nervous system (CNS) and also to serve as a coreceptor for the entry of human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus (SIV). Studies with animal models suggested that APJ and its natural ligand, apelin, play an important role in the central control of body fluid homeostasis, and in regulation of blood pressure and cardiac contractility. In this study, we characterize the structural and functional determinants of the N-terminal domain of APJ in interactions with its natural ligand and HIV-1 envelope glycoprotein. We demonstrate that the second 10 residues of the N-terminal domain of APJ are critical for association with apelin, while the first 20 amino acids play an important role in supporting cell-cell fusion mediated by HIV-1 gp120. With site-directed mutagenesis, we have identified that the negatively charged amino acid residues Glu20 and Asp23 are involved in receptor and coreceptor functions, but residues Tyr10 and Tyr11 substantially contribute to coreceptor function for both T-tropic (CXCR4) and dual-tropic (CXCR4 and CCR5) HIV-1 isolates. Thus, this study provides potentially important information for further characterizing APJ-apelin functions in vitro and in vivo and designing small molecules for treatment of HIV-1 infection in the CNS.
Zhou
Naiming
N
Dorrance H. Hamilton Laboratories, Center for Human Virology and Biodefense, Division of Infectious Diseases and Environmental Medicine, Department of Medicine, Jefferson Medical College, Philadelphia, PA 19107, USA.
Zhang
Xiaoling
X
Fan
Xuejun
X
Argyris
Elias
E
Fang
Jianhua
J
Acheampong
Edward
E
DuBois
Garrett C
GC
Pomerantz
Roger J
RJ
D000595:Amino Acid Sequence; D000073861:Apelin; D000075244:Apelin Receptors; D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D002490:Central Nervous System / Q000378:metabolism*; D017353:Gene Deletion; D015699:HIV Envelope Protein gp120 / Q000378:metabolism*; D015497:HIV-1 / Q000378:metabolism / Q000472:pathogenicity*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D015728:Receptors, HIV / Q000378:metabolism*; D015398:Signal Transduction; D013329:Structure-Activity Relationship
C115436:APLN protein, human; C104575:APLNR protein, human; D000073861:Apelin; D000075244:Apelin Receptors; D002352:Carrier Proteins; D015699:HIV Envelope Protein gp120; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D043562:Receptors, G-Protein-Coupled; D015728:Receptors, HIV