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A hydrodynamic analysis of APOBEC3G reveals a monomer-dimer-tetramer self-association that has implications for anti-HIV function.

ABSTRACT: The innate antiviral factor APOBEC3G (A3G) possesses RNA binding activity and deaminates HIV-1 DNA. High-molecular mass forms of A3G can be isolated from a variety of cell types but exhibit limited deaminase activity relative to low-molecular mass species prepared under RNA-depleted conditions. To investigate the fundamental oligomeric state and shape of A3G, we conducted sedimentation velocity analyses of the pure enzyme under RNA-deficient conditions. The results reveal a predominant dimer in equilibrium with minor monomeric and tetrameric species. Hydrodynamic modeling of the dimer supports an extended cylindrical shape that assembles into an elongated tetramer. Overall, the results provide physical restraints for the A3G quaternary structure that have implications for modulating antiviral function.

SUBMITTER: Salter JD

PROVIDER: S-EPMC2783380 | biostudies-literature | 2009 Nov

REPOSITORIES: biostudies-literature

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A hydrodynamic analysis of APOBEC3G reveals a monomer-dimer-tetramer self-association that has implications for anti-HIV function.

Salter Jason D JD Krucinska Jolanta J Raina Jay J Smith Harold C HC Wedekind Joseph E JE

Biochemistry 20091101 45

The innate antiviral factor APOBEC3G (A3G) possesses RNA binding activity and deaminates HIV-1 DNA. High-molecular mass forms of A3G can be isolated from a variety of cell types but exhibit limited deaminase activity relative to low-molecular mass species prepared under RNA-depleted conditions. To investigate the fundamental oligomeric state and shape of A3G, we conducted sedimentation velocity analyses of the pure enzyme under RNA-deficient conditions. The results reveal a predominant dimer in ...[more]

PMID: 19839647

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Project description:The ground-state properties of (NO)(2) and (NO)(4) have been investigated using multireference second-order perturbation theory (MRMP2) and include a two-tier extrapolation to the complete basis set (CBS) limit. For the NO dimer the MRMP2(18,14)/CBS predicted structure, binding energy (with respect to 2NO; D(e) = 3.46 kcal/mol), and dipole moment (u(e) = 0.169 D) are in excellent agreement with experimental measurements (D(e) = 2.8-3.8 kcal/mol; u(e) = 0.171 D). Additionally, three of four intermolecular anharmonic MRMP2(18,14)/CBS-estimated frequencies (143 cm(-1), 238 cm(-1), 421 cm(-1)) are in excellent agreement with recent gas-phase experimental measurements (135 cm(-1), 239 cm(-1), 429/428 cm(-1)); however, the predicted value of 151 cm(-1) for the out-of-plane torsion (A(2)) is elevated compared to recent experimental estimates of 97-117 cm(-1). Our finding that this infrared-forbidden vibration is also predicted to have an extremely low Raman activity (0.04 Å/amu at the MP2/QZ level of theory) conflicts with Raman measurements of a strong intensity for a low frequency band; however, these studies were performed for low temperature solid and liquid phases. Probing the possibility of the presence of higher order clusters we investigated the stability of (NO)(4) and discovered three isomers, each resembling pairs of dimers, that were stable to dissociation to 2(NO)(2), with the lowest-energy isomer (C(i) structure) having a predicted binding energy almost identical to that of the dimer. Computed vibrational frequencies of the C(i) isomer indicate that the 12 highest-frequency modes resemble barely shifted NO dimer-combined bands while the 13th highest-frequency mode at ~100 cm(-1) is exclusive to (NO)(4). Moreover, this tetramer-unique vibration is infrared inactive but has a very high predicted Raman activity of some 24 Å/amu. Guided by the theoretical results, we reexamined and reassigned experimental Raman and infrared data going back to 1951 and determined that our best predictions of vibrational frequencies of (NO)(2) and (NO)(4) are consistent with experimental observations. We thus postulate the existence and observation of (NO)(4).

Dataset Information

A hydrodynamic analysis of APOBEC3G reveals a monomer-dimer-tetramer self-association that has implications for anti-HIV function.

Publications

A hydrodynamic analysis of APOBEC3G reveals a monomer-dimer-tetramer self-association that has implications for anti-HIV function.

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