The Autism and Angelman Syndrome Protein Ube3A/E6AP: The Gene, E3 Ligase Ubiquitination Targets and Neurobiological Functions

Abstract

UBE3A is a gene implicated in neurodevelopmental disorders. The protein product of UBE3A is the E3 ligase E6-associated protein (E6AP), and its expression in the brain is uniquely regulated via genetic imprinting. Loss of E6AP expression leads to the development of Angelman syndrome (AS), clinically characterized by lack of speech, abnormal motor development, and the presence of seizures. Conversely, copy number variations (CNVs) that result in the overexpression of E6AP are strongly associated with the development of autism spectrum disorders (ASDs), defined by decreased communication, impaired social interest, and increased repetitive behavior. In this review article, we focus on the neurobiological function of Ube3A/E6AP. As an E3 ligase, many functional target proteins of E6AP have been discovered, including p53, Arc, Ephexin5, and SK2. On a neuronal level, E6AP is widely expressed within the cell, including dendritic arbors, spines, and the nucleus. E6AP regulates neuronal morphological maturation and plays an important role in synaptic plasticity and cortical development. These molecular findings provide insight into our understanding of the molecular events underlying AS and ASDs.

Keywords: Angelman syndrome (AS); UBE3A (E6AP); autism (ASD); dendritic pruning; neurodevelopement; synaptic plasiticty; ubiquitination.

Figure 1

UBE3A imprinting and E6-associated protein (E6AP) structure. (A) The UBE3A gene is located on chromosome 15 within the region of 15q11-15q13. (B) Within the chromosome region 15q11-q13, the gene UBE3A is maternally imprinted in the brain. A paternally expressed antisense transcript (UBE3A-ATS) initiates at the unmethylated imprinting center (IC, red circle) of the paternal allele and overlaps UBE3A, silencing the paternal expression of the gene in the brain. This imprinting results in expression solely from the maternal allele in the brain, as the maternal imprinting center is methylated (IC, green circle). (C) E6AP is an 862-amino acid protein with a C-terminal homology to E6AP C-terminus (HECT) E3 ligase domain. It also contains a binding site for the human papillomavirus type 16 (HPV16) protein E6 (E6 BS). The catalytic cysteine of E6AP is located at C820 (red).

Figure 2

E3 ligases and the ubiquitin proteasome system. Proteasome-mediated degradation of proteins involves the addition of ubiquitin to specific target molecules followed by their trafficking to the proteasome for degradation into small peptides and amino acids. This process occurs via coordinated actions of three classes of enzymes: E1, E2, and E3. The ubiquitin-activating enzyme E1, activates the free ubiquitin in an ATP-dependent manner. The conjugating enzyme E2 then carries the transfer of the activated ubiquitin, and a substrate-specific E3 ligase attaches the ubiquitin molecule to a target protein. Once a ubiquitin molecule has attached to a protein, another ubiquitin can be attached to an internal lysine residue of the first ubiquitin, and this can go on to form a polyubiquitin chain on the target protein. Known E6AP targets include p53, Arc, Ephexin5, and SK2. Polyubiquitination tags a protein substrate for degradation and causes it to be trafficked to the 26S proteasome.