CCR2 and CCR5 receptor-binding properties of herpesvirus-8 vMIP-II based on sequence analysis and its solution structure.
Human herpesvirus-8 (HHV-8) is the infectious agent responsible for Kaposi's sarcoma and encodes a protein, macrophage inflammatory protein-II (vMIP-II), which shows sequence similarity to the human CC chemokines. vMIP-II has broad receptor specificity that crosses chemokine receptor subfamilies, and inhibits HIV-1 viral entry mediated by numerous chemokine receptors. In this study, the solution structure of chemically synthesized vMIP-II was determined by nuclear magnetic resonance. The protein is a monomer and possesses the chemokine fold consisting of a flexible N-terminus, three antiparallel beta strands, and a C-terminal alpha helix. Except for the N-terminal residues (residues 1-13) and the last two C-terminal residues (residues 73-74), the structure of vMIP-II is well-defined, exhibiting average rmsd of 0.35 and 0.90 A for the backbone heavy atoms and all heavy atoms of residues 14-72, respectively. Taking into account the sequence differences between the various CC chemokines and comparing their three-dimensional structures allows us to implicate residues that influence the quaternary structure and receptor binding and activation of these proteins in solution. The analysis of the sequence and three-dimensional structure of vMIP-II indicates the presence of epitopes involved in binding two receptors CCR2 and CCR5. We propose that vMIP-II was initially specific for CCR5 and acquired receptor-binding properties to CCR2 and other chemokine receptors.
Shao
W
W
Walt Disney Memorial Cancer Institute at Florida Hospital, Orlando, FL, USA.
Fernandez
E
E
Sachpatzidis
A
A
Wilken
J
J
Thompson
D A
DA
Schweitzer
B I
BI
Lolis
E
E
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D018925:Chemokines / Q000737:chemistry* / Q000378:metabolism*; D019742:Chemokines, CC / Q000737:chemistry*; D019281:Dimerization; D000939:Epitopes; D009682:Magnetic Resonance Spectroscopy; D008956:Models, Chemical; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010452:Peptide Biosynthesis; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D054390:Receptors, CCR2; D019713:Receptors, CCR5 / Q000737:chemistry* / Q000378:metabolism; D019707:Receptors, Chemokine / Q000737:chemistry* / Q000378:metabolism; D020539:Sequence Analysis, Protein; D017386:Sequence Homology, Amino Acid
C515334:CCR2 protein, human; D018925:Chemokines; D019742:Chemokines, CC; D000939:Epitopes; D054390:Receptors, CCR2; D019713:Receptors, CCR5; D019707:Receptors, Chemokine; C108059:vMIP-II