Architecture and Assembly of HIV Integrase Multimers in the Absence of DNA Substrates.

Fox Chase Cancer Center, United States
Journal of Biological Chemistry (Impact Factor: 4.6). 01/2013; DOI: 10.1074/jbc.M112.434431
Source: PubMed

ABSTRACT have applied small angle X-ray scattering (SAXS) and protein cross-linking coupled with mass spectrometry to determine the architectures of full-length HIV integrase (IN) dimers in solution. By blocking interactions that stabilize either a core-core domain interface or N-terminal domain (NTD) intermolecular contacts, we show that full-length HIV IN can form two dimer types. One is an expected dimer, characterized by interactions between two catalytic core domains. The other dimer is stabilized by interactions of the NTD of one monomer with the C-terminal domain (CTD) and catalytic core domain of the second monomer, as well as direct interactions between the two CTDs. This organization is similar to the "reaching dimer" previously described for wild type ASV apo-IN, and resembles the inner, substrate-binding dimer in the crystal structure of the PFV intasome. Results from our SAXS and modeling studies indicate that in the absence of its DNA substrate, the HIV IN tetramer assembles as two stacked reaching dimers that are stabilized by core-core interactions. These models of full-length HIV IN provide new insight into multimer assembly and suggest additional approaches for enzyme inhibition.

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