The structural basis for molecular recognition of the capsid protein of human immunodeficiency virus type 1 by human Cyclophilin A.

The human protein, Cyclophilin A, is a member of a family of enzymes, known as peptidyl-prolyl isomerases, which catalyze cis-trans isomerization of proline peptide bonds. Because proline isomerization is a rate limiting step in the refolding of some proteins, Cyclophilin A has been widely believed to function as a catalyst of protein folding in vivo. Recently, Cyclophilin A has been found to associate with the capsid protein of human immunodeficiency virus type 1, and is packaged via this interaction into budding virus particles. This packaging is necessary for viral infectivity. The work presented here addresses two fundamental questions. First, what are the molecular details of this molecular recognition event? Second, what role might Cyclophilin A play in the viral life cycle? The Cyclophilin A binding site on capsid was identified, and the structure of Cyclophilin A complexed with a synthetic hexapeptide corresponding to this sequence was determined by X-ray crystallography. Additionally, the crystal structure of Cyclophilin A complexed with the 151 amino acid residue amino terminal domain of capsid was determined. Together, these structures indicate that Cyclophilin A recognizes capsid in a sequence dependent manner, and present a rationalization for Cyclophilin A's sequence independent proline isomerization activity. Comparison of the solution structure of the amino-terminal domain of capsid with the structure in complex with Cyclophilin A indicates that Cyclophilin A binding does not cause large scale conformational changes in capsid. A model is proposed in which Cyclophilin A functions as a disassembly factor in the viral life cycle.