Hect domain

Adaptor Proteins. Figure 1 Adaptor protein domains. A scheme of the domain structures of some well-characterized adaptor proteins is shown. Descriptions of domain characteristics are in main text except C2, binds to phospholipids GTPase activating protein (GAP) domain, inactivates small GTPases such as Ras Hect domain, enzymatic domain of ubiquitin ligases and GUK domain, guanylate kinase domain. For clarity, not all domains contained within these proteins are shown. 

As HECT domain function was being elucidated, studies in the mid-1990s on cell-cycle regulation led to the initial description of SCF E3s. These were first characterized as containing Skpl, Cullin-1, and an F-box-containing protein [16, 17]. 

Also identified during the mid-1990s was the APC (anaphase promoting complex - also known as the cyclosome), another multi-subunit cullin-containing E3 that mediates ubiquitylation of mitotic cyclins [18, 19]. Mdm2, initially thought to be a HECT domain variant, was shown in 1997 to have E3 activity towards p53 in vitro [20]. For the non-HECT E3s no common structural feature had been detected. Thus, by 1997 the only defined molecular signature for E3 activity was the HECT domain. 

After E2/ubiquitin thiol ester formation, the ubiquitin must be transferred to the substrate, which is sometimes another ubiquitin. An E3 is usually required for this reaction in vitro, and is always required in vivo. There are three known types of E3s the RING domain, HECT domain, and U-box (UED2 homology) families. RING and U-box E3s act as bridging factors for E2s and substrates, but HEGT E3s use a different mechanism, adding an extra step to the pathway (Section 5.6.3.3). 

The E6AP HECT Domain in Complex With UbcH7... 

Similar to other HECT E3s, E6AP consists of a - 40-kDa C-terminal HECT domain and an N-terminal region containing sequences involved in binding E6-p53,... 

Fig. 7.3. Conformational changes and E2-binding specificity of the HECTdomain. (A) Schematic diagram of the structures of E6AP and WWPl HECT domains with their N-lobes superimposed indicating the potential large domain movement of the HECT E3. (B)...

Surface representation of the E6AP HECT domain, showing that conserved HECT domain residues map to the catalytic cleft defined by... 

Schwarz, S. E., Rosa, J. L. and Scheffner, M. Characterization of human hect domain family members and their interaction with UbcH5 and UbcH7. J Biol Chem 1998, 273, 12148-54. 

Verdecia, M. a. et al. Conformational flexibility underlies ubiquitin ligation mediated by the WWPl HECT domain E3 ligase. Mol Cdl 2003, 11, 249-59. 

You, J. and Pickaet, C. M. A HECT domain E3 enzyme assembles novel polyubiquitin chains, J Biol Chem, 2001, 276, 19871-8. 

Hul5 is a stoichiometric component of affinity-purified yeast 26S proteasomes purified under low-salt conditions [80], Hul5 is a HECT-domain E3 ligase known as KIAAIO in mammals. It assembles both K48- and K29-linked polyubiquitin chains and binds to PA700 and to isolated Rpnl/S2 via an N-terminal domain... 

There are three major classes of E3s (1) HECT domain E3s, (2) really interesting new gene (RING) finger E3s, and (3) complex multisubunit E3s (Figure 4). 

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