Protein degradation is employed in both regulation and quality control. 
Regulated degradation of specific proteins is often mediated by discrete regions 
of primary sequence known as degrons, whereas protein quality control involves 
recognition of structural features common to damaged or misfolded proteins, 
rather than specific features of an individual protein. The yeast HMG-CoA 
reductase isozyme Hmg2p undergoes stringently regulated degradation by machinery 
that is also required for ER quality control. The 523 residue N-terminal 
transmembrane domain of Hmg2p is necessary and sufficient for regulated 
degradation. To understand how Hmg2p undergoes regulated degradation by the ER 
quality control pathway, we analyzed over 300 mutants of Hmg2p. Regulated 
degradation of Hmg2p requires information distributed over the entire 
transmembrane domain. Accordingly, we refer to this determinant as a 
'distributed' degron, which has functional aspects consistent with both 
regulation and quality control. The Hmg2p degron functions in the specific, 
regulated degradation of Hmg2p and can impart regulated degradation to fusion 
proteins. However, its recognition is based on dispersed structural features 
rather than primary sequence motifs. This mode of targeting has important 
consequences both for the prediction of degradation substrates and as a 
potential therapeutic strategy for targeted protein degradation using endogenous 
degradation pathways.