A 'distributed degron' allows regulated entry into the ER degradation pathway

Protein degradation is employed in both regulation and quality control. Reg ulated degradation of specific proteins is often mediated by discrete regio ns of primary sequence known as degrons, whereas protein quality control in volves recognition of structural features common to damaged or misfolded pr oteins, rather than specific features of an individual protein. The yeast H MG-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 re gulated degradation. To understand how Hmg2p undergoes regulated degradatio n by the ER quality control pathway, we analyzed over 300 mutants of Hmg2p, Regulated degradation of Hmg2p requires information distributed over the e ntire transmembrane domain. Accordingly, we refer to this determinant as a 'distributed' degron, which has functional aspects consistent with both reg ulation and quality control. The Hmg2p degron functions in the specific, re gulated degradation of Hmg2p and can impart regulated degradation to fusion proteins. However, its recognition is based on dispersed structural featur es rather than primary sequence motifs. This mode of targeting has importan t consequences both for the prediction of degradation substrates and as a p otential therapeutic strategy for targeted protein degradation using endoge nous degradation pathways.