Insights into the Structures and Multimeric Status of APOBEC Proteins Involved in Viral Restriction and Other Cellular Functions.

Xiaojiang S Chen

doi:10.3390/v13030497

Abstract

Apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC) proteins belong to a family of deaminase proteins that can catalyze the deamination of cytosine to uracil on single-stranded DNA or/and RNA. APOBEC proteins are involved in diverse biological functions, including adaptive and innate immunity, which are critical for restricting viral infection and endogenous retroelements. Dysregulation of their functions can cause undesired genomic mutations and RNA modification, leading to various associated diseases, such as hyper-IgM syndrome and cancer. This review focuses on the structural and biochemical data on the multimerization status of individual APOBECs and the associated functional implications. Many APOBECs form various multimeric complexes, and multimerization is an important way to regulate functions for some of these proteins at several levels, such as deaminase activity, protein stability, subcellular localization, protein storage and activation, virion packaging, and antiviral activity. The multimerization of some APOBECs is more complicated than others, due to the associated complex RNA binding modes.

Highlights

There are eleven members of Apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC) proteins in humans (Figure 1A)
Unlike most other APOBEC members, A2 is well-behaved during purification, likely because A2 does not bind to cellular RNAs
At this point, more data will be needed to address these fascinating questions about the functional relationship of domain orientation of A3G, which could be relevant to other double-domain APOBEC members as well

Summary

Introduction

There are eleven members of APOBEC (abbreviated from apolipoprotein B mRNA editing catalytic polypeptide-like) proteins in humans (Figure 1A). Unlike most other APOBEC members, A2 is well-behaved during purification, likely because A2 does not bind to cellular RNAs. Despite the structural and biochemical data available to date, the functional oligomeric forms of A2 or whether A2 needs to form complexes with other cellular proteins for function requires further investigation. Given the highly active deaminase activities of A3A on ssDNA and RNA, it still remains to be seen if the apo-A3A dimer has a regulatory role or whether A3A interacts with cellular proteins to form functional complex for regulation of A3A activity, subcellular localization or/and turnover rate. The dsRNA-binding defective A3H mutants show a shift of subcellular localization from the cytosol to the nucleus, generating genomic mutations with the elevated deaminase activity Some of these RNA binding mutants become less stable in cells, indicating a role in enhancing the stability of A3H through dimerization. R26 on A3H loop 1 is shown to be involved in RNA binding, ssDNA substrate interaction, and deaminase activity [148]

Double-Domain A3s

Findings

Summary