MEMBRANE-PROXIMAL TYROSINE-BASED SIGNAL MEDIATES INTERNALIZATION OF THE HIV-1 ENVELOPE GLYCOPROTEIN VIA INTERACTION WITH THE AP-2 CLATHRIN ADAPTER

The envelope glycoprotein (Env) of human immunodeficiency virus, type 1 (HIV-1) undergoes rapid internalization after its transport to the c ell surface. Env internalization is dependent upon information contain ed within the cytosolic domain of the protein, Here, we report that th e cytosolic domain of Env binds specifically to the medium chain, mu 2 , of the clathrin-associated protein complex AP-2, as well as to the c omplete AP-2 complex. The Env cytosolic domain contains two highly con served tyrosine-based motifs ((YSPL)-S-712 and (YHRL)-H-768), both of which are capable of binding to mu 2 when presented as short peptides, However, only the membrane-proximal motif (YSPL)-S-712 binds to mu 2 and is required for internalization in the context of the whole cytoso lic domain of Env, A glycine residue (Gly(711)) adjacent to the (YSPL) -S-712 motif is also important for binding to mu 2/AP-2 and internaliz ation. These observations suggest that the accessibility of the membra ne-proximal GY(712)SPL to mu 2/AP-2 determines its function as a signa l for recruitment of HIV-1 Env into clathrin-coated pits and its ensui ng internalization.