A natural CCL5/RANTES variant antagonist for CCR1 and CCR3.
The N-terminal domain of the chemokine CCL5/regulated upon activation normal T cell expressed and secreted (RANTES) has been shown to be critical for its biological activity on leukocytes. Several N-terminus-modified CCL5/RANTES derivatives, such as N-Terminal truncated CCL5/RANTES, Met-RANTES, and amino-oxypentane (AOP)-RANTES exhibited antagonist or partial agonist functions when investigated on the properties of their receptors CCR1, CCR3, and CCR5. Studying 95 African samples from Cameroon, we found a naturally occurring variant of CCL5/RANTES containing a missense mutation located in the first amino acid of the secreted form (S24F). S24F binds CCR1, CCR3, and CCR5 and triggers receptor down-modulation comparable to CCL5/RANTES. Moreover, in CCR5 positive cells, S24F elicits cellular calcium mobilization equivalent to that obtained with CCL5/RANTES. By contrast, S24F does not provoke any response in CCR1 and CCR3 positive cells. As CCL5/RANTES is able to attract different subtypes of leukocytes into inflamed tissue and intervenes in a wide range of allergic and autoimmune diseases, the discovery of this natural N-terminus-modified CCL5/RANTES analogue exhibiting differential effects on CCL5/RANTES receptors, opens up additional perspectives for therapeutic intervention.
Capoulade-Métay
Corinne
C
INSERM U543, CHU Pitié-Salpêtrière, 91 Boulevard de l'Hôpital, 75013 Paris, France. cmetay@hotmail.com
Ayouba
Ahidjo
A
Kfutwah
Anfumbom
A
Lole
Kavita
K
Pêtres
Stéphane
S
Dudoit
Yasmine
Y
Deterre
Philippe
P
Menu
Elisabeth
E
Barré-Sinoussi
Françoise
F
Debré
Patrice
P
Theodorou
Ioannis
I
D000595:Amino Acid Sequence; D001681:Biological Assay; D002118:Calcium / Q000032:analysis; D002163:Cameroon; D018946:Chemokine CCL5 / Q000235:genetics* / Q000378:metabolism; D019742:Chemokines, CC / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D011110:Polymorphism, Genetic; D017434:Protein Structure, Tertiary / Q000235:genetics; D054389:Receptors, CCR1; D054397:Receptors, CCR3; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016415:Sequence Alignment
C483024:CCL5 protein, human; C515300:CCR1 protein, human; C515350:CCR3 protein, human; D018946:Chemokine CCL5; D019742:Chemokines, CC; D054389:Receptors, CCR1; D054397:Receptors, CCR3; D019707:Receptors, Chemokine; D002118:Calcium