Tyrosine-sulfated peptides functionally reconstitute a CCR5 variant lacking a critical amino-terminal region.
Entry of most primary human immunodeficiency virus, type 1 (HIV-1) isolates into their target cells requires the cellular receptor CD4 and the G protein-coupled chemokine coreceptor CCR5. An acidic, tyrosine-rich, and tyrosine-sulfated domain of the CCR5 amino terminus plays a critical role in the ability of CCR5 to serve as an HIV-1 coreceptor, and tyrosine-sulfated peptides based on this region physically associate with the HIV-1 envelope glycoprotein gp120 and slow HIV-1 entry into CCR5-expressing cells. Here we show that the same tyrosine-sulfated peptides, but not their unsulfated analogs, can restore the HIV-1 coreceptor activity of a CCR5 variant lacking residues 2-17 of its amino terminus. Additionally, these sulfated peptides restored the ability of this CCR5 variant to mobilize calcium in response to the chemokines macrophage inflammatory factors 1alpha and 1beta. These observations show that a tyrosine-sulfated region of the CCR5 amino terminus can function independently to mediate association of chemokines and the HIV-1 envelope glycoprotein with the remaining domains of CCR5.
Department of Cancer Immunology and AIDS, Dana Farber Cancer Institute, Department of Pathology, Division of AIDS, Harvard Medical School, Boston, MA 02115, USA.
Michael
M
Farzan
Susan
S
Chung
Wenhui
W
Li
Natalya
N
Vasilieva
Paulette L
PL
Wright
Christine E
CE
Schnitzler
Robb J
RJ
Marchione
Craig
C
Gerard
Norma P
NP
Gerard
Joseph
J
Sodroski
Hyeryun
H
Choe
D000595:Amino Acid Sequence; D002118:Calcium / Q000378:metabolism; D015497:HIV-1 / Q000378:metabolism; D008969:Molecular Sequence Data; D010455:Peptides / Q000378:metabolism*; D019713:Receptors, CCR5 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013431:Sulfates / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism*
D010455:Peptides; D019713:Receptors, CCR5; D013431:Sulfates; D014443:Tyrosine; D002118:Calcium