At the moment, it is unintuitive to
conceive a straightforward mechanism
whereby autoubiquitination of a soluble
domain can influence the conformationof a lipid-embedded channel. Autou-
biquitination, as a hallmark of RING-
bearing ubiquitin ligases, was known for
years , but only recently researchers
found that autoubiquitination can have
a positive function other than destabi-
lizing the modified ligase. This often
requires a cofactor that use a ubiquitin-
binding domain to ‘decipher’ the
ubiquitin signal on ligase . Thus, the
transmembrane segments of Hrd1 may
collectively form a ubiquitin-binding
site on the ER surface. Alternatively,
ubiquitin conjugates may allosterically
alter the conformation of the Hrd1 trans-
membrane segments. Further elucida-
tion of this gating mechanism requires
determination of Hrd1 structures in
unmodified and modified states, which
would have been a huge challenge in
the past. Fortunately, with the recent
advancement of the high-resolution
electron microscopy technology, we
may not need to wait long for an answer.