The multifaceted roles of RNA binding in APOBEC cytidine deaminase functions

Advanced Review

Kimberly M. Prohaska, Ryan P. Bennett, Jason D. Salter, Harold C. Smith

Published Online: Mar 24 2014

DOI: 10.1002/wrna.1226

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Cytidine deaminases have important roles in the regulation of nucleoside/deoxynucleoside pools for DNA and RNA synthesis. The APOBEC family of cytidine deaminases (named after the first member of the family that was described, Apolipoprotein B mRNA Editing Catalytic Subunit 1, also known as APOBEC1 or A1) is a fascinating group of mutagenic proteins that use RNA and single‐stranded DNA (ssDNA) as substrates for their cytidine or deoxycytidine deaminase activities. APOBEC proteins and base‐modification nucleic acid editing have been the subject of numerous publications, reviews, and speculation. These proteins play diverse roles in host cell defense, protecting cells from invading genetic material, enabling the acquired immune response to antigens and changing protein expression at the level of the genetic code in mRNA or DNA. The amazing power these proteins have for interphase cell functions relies on structural and biochemical properties that are beginning to be understood. At the same time, the substrate selectivity of each member in the family and their regulation remains to be elucidated. This review of the APOBEC family will focus on an open question in regulation, namely what role the interactions of these proteins with RNA have in editing substrate recognition or allosteric regulation of DNA mutagenic and host‐defense activities. WIREs RNA 2014, 5:493–508. doi: 10.1002/wrna.1226 This article is categorized under: RNA Interactions with Proteins and Other Molecules > Protein–RNA Recognition RNA Interactions with Proteins and Other Molecules > Small Molecule–RNA Interactions RNA Processing > RNA Editing and Modification Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs

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The ZDD of the APOBEC family. (a) The ZDD sequence motif [(H/C)‐x‐E‐x_(25–30)‐P‐C‐xx‐C] is conserved throughout the APOBEC family of cytidine deaminases. Several APOBEC3 members (B, DE, F, and G) have two ZDD motifs in tandem on a single polypeptide. (b) The CDA domains of the A3 family members are subcategorized as Z1, Z2, or Z3 type according to additional conserved sequences within the ZDD motif.

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Important functional domains of A3G. (a) Schematic of full‐length A3G protein highlighting the regions comprising the two ZDDs (N‐terminal ZDD spans residues 65–100, C‐terminal ZDD spans residues 257–291). (b) Separation of A3Gs N‐ and C‐termini to highlight the characteristics and functions of each half of the protein. The N‐terminal half of A3G is required for both RNA binding (residues 24–136) and RNA bridged A3G multimerization (residues 22–127). Residues 122–127 have been suggested to mediate N‐terminal dimerization of A3G in a head‐to‐head fashion. The C‐terminal portion of A3G is required for its ssDNA binding and deaminase activity (residues 215–374 and 211–375, respectively). The C‐terminus is also responsible for A3G tail‐to‐tail dimerization (residues 215–374). (c) Representation of the A3G domains required for interaction with viral proteins and cellular localization. The cytoplasmic retention signal (CRS) of A3G is located in the N‐terminal half of the protein, requiring residues 19–32 and 113–128. A3G incorporation with virions requires an interaction with the HIV Gag protein, which is facilitated by multiple regions of the N‐terminal domain (residues 19–30, 94–127, 157–181). In addition to Gag binding, the N‐terminal domain of A3G has been shown to interact with HIV Vif (residues 32–136). Upon binding to Vif, A3G is ubiquitinated (Ub) at C‐terminal lysine residues, including K297, K301, K303, and K334.

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Representative APOBEC crystal structures. Diagram of a representative crystal structure of (a) the C‐terminal Z1‐type CDA of A3G (PDB 3IR2) at 2.25 Å resolution and (b) the C‐terminal Z‐2 type CDA of A3F (PDB 4IOU) at 2.75 Å resolution. The αβα supersecondary structural element (green) is shown embedded within the core CDA fold, comprising the five‐stranded, mixed β‐sheet surrounded by six α‐helices, typical of the A3 family. Sidechains of the conserved zinc‐binding residues and proton‐shuttling glutamic acid are illustrated in red and orange, respectively. The catalytic zinc ion is represented as a purple sphere. The additional non‐catalytic zinc ion present in the A3G structure is represented by the yellow sphere; it is coordinated by four residues, two from each of adjacent subunits within the crystal and may be an artifact due to crystal packing. The β2 bulge between β2 and β2′ is present in the structure of the Z1‐type CDA of the A3G C‐terminal CDA (a), but is noticeably absent from the Z2‐type CDA of the A3F C‐terminal CDA (b).

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