A mutant of melanoma growth stimulating activity does not activate neutrophils but blocks erythrocyte invasion by malaria.
Alanine scanning mutagenesis of the charged amino acids of melanoma growth stimulating activity (MGSA) was used to identify specific residues that are involved in binding to the human erythrocyte Duffy antigen/chemokine receptor (DARC) and to the type B interleukin-8 receptor (IL-8RB) on neutrophils. Receptor binding and biological studies with the alanine scan mutants of MGSA demonstrate that MGSA binds to DARC and the IL-8RB through distinct binding regions. One of the MGSA mutants, E6A, binds to human erythrocytes and is able to inhibit malaria invasion as efficiently as wild type MGSA but has a severely reduced ability to bind to or signal through the IL-8RB. Mutant chemokines like E6A could prove to be useful therapeutically for the design of receptor blocking drugs that inhibit erythrocyte invasion by Plasmodium vivax malaria.
Hesselgesser
J
J
Genentech, Inc., South San Francisco, California 94080, USA.
Chitnis
C E
CE
Miller
L H
LH
Yansura
D G
DG
Simmons
L C
LC
Fairbrother
W J
WJ
Kotts
C
C
Wirth
C
C
Gillece-Castro
B L
BL
Horuk
R
R
D000409:Alanine; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D054360:Chemokine CXCL1; D019743:Chemokines, CXC; D002630:Chemotactic Factors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D003001:Cloning, Molecular; D017124:Conserved Sequence; D004375:Duffy Blood-Group System / Q000378:metabolism; D004912:Erythrocytes / Q000187:drug effects / Q000469:parasitology*; D004926:Escherichia coli; D006133:Growth Substances / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D007668:Kidney; D007700:Kinetics; D008288:Malaria / Q000097:blood; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009363:Neoplasm Proteins / Q000378:metabolism / Q000494:pharmacology; D018375:Neutrophil Activation; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology*; D016790:Plasmodium knowlesi / Q000187:drug effects / Q000472:pathogenicity*; D011487:Protein Conformation; D018121:Receptors, Cytokine / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D017386:Sequence Homology, Amino Acid; D014162:Transfection
C475829:CXCL1 protein, human; D054360:Chemokine CXCL1; D019743:Chemokines, CXC; D002630:Chemotactic Factors; D004375:Duffy Blood-Group System; D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins; D018121:Receptors, Cytokine; D011994:Recombinant Proteins; C078862:melanoma growth stimulating activity receptor; D000409:Alanine