HECT E3s and human disease - PubMed (original) (raw)

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HECT E3s and human disease

Martin Scheffner et al. BMC Biochem. 2007.

Abstract

In a simplified view, members of the HECT E3 family have a modular structure consisting of the C-terminal HECT domain, which is catalytically involved in the attachment of ubiquitin to substrate proteins, and N-terminal extensions of variable length and sequence that mediate the substrate specificity of the respective HECT E3. Although the physiologically relevant substrates of most HECT E3s have remained elusive, it is becoming increasingly clear that HECT E3s play an important role in sporadic and hereditary human diseases including cancer, cardiovascular (Liddle's syndrome) and neurological (Angelman syndrome) disorders, and/or in disease-relevant processes including bone homeostasis, immune response and retroviral budding. Thus, molecular approaches to target the activity of distinct HECT E3s, regulators thereof, and/or of HECT E3 substrates could prove valuable in the treatment of the respective diseases. Publication history: Republished from Current BioData's Targeted Proteins database (TPdb; http://www.targetedproteinsdb.com).

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Figures

Figure 1

Figure 1

The family of HECT E3s. All members of the HECT E3 family are characterized by the C-terminal HECT domain, which consists of approximately 350 amino acid residues and represents the catalytic domain. The HERC family comprises six members, which are characterized by the presence of one or several RLD domains (as representative, the structure of HERC5 is schematically shown). The Nedd4/Nedd4-like family has nine members that are characterized by an N-terminal C2 domain and the presence of several WW domains (as representative, the schematic structure of Smurf2 is shown). The schematic structure of E6-AP, the founding member of the HECT E3 family, is shown as representative of the third subfamily (“E6” denotes the binding site of E6-AP for the HPV E6 oncoprotein). Members of this subfamily (SI-HECT E3s) are characterized by the notion that they contain neither RLDs nor WW domains.

Figure 2

Figure 2

Role of Smurfs in the TGF-β/BMP pathways. TGF-β ligand stimulates heterodimerization of type I and type II Ser/Thr kinase receptors (labeled R-I and R-II), leading to phosphorylation of type I receptor by type II receptor. This recruits receptor regulated Smads (R-Smads), which become phosphorylated. Upon phosphorylation, R-Smads interact with the common Smad (co-Smad), Smad4, and the complex translocates into the nucleus, where it interacts with co-factors and stimulates transcription of genes involved in differentiation. The pathway is negatively regulated by inhibitory Smads (I-Smads), by SnoN and by Smurfs. Smurfs can interact with and ubiquitylate R-Smads and can be recruited by I-Smads to the receptor, where they induce receptor ubiquitylation and internalization. Furthermore, Smurfs are also involved in SnoN ubiquitylation, and thus are also able to act as positive regulators of this pathway.

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