An autonomous, but INSIG-modulated, role for the sterol sensing domain in mallostery-regulated ERAD of yeast HMG-CoA reductase.

ABSTRACT: HMG-CoA reductase (HMGR) undergoes feedback-regulated degradation as part of sterol pathway control. Degradation of the yeast HMGR isozyme Hmg2 is controlled by the sterol pathway intermediate GGPP, which causes misfolding of Hmg2, leading to degradation by the HRD pathway; we call this process mallostery. We evaluated the role of the Hmg2 sterol sensing domain (SSD) in mallostery, as well as the involvement of the highly conserved INSIG proteins. We show that the Hmg2 SSD is critical for regulated degradation of Hmg2 and required for mallosteric misfolding of GGPP as studied by in vitro limited proteolysis. The Hmg2 SSD functions independently of conserved yeast INSIG proteins, but its function was modulated by INSIG, thus imposing a second layer of control on Hmg2 regulation. Mutant anal

SUBMITTER: Wangeline MA 

PROVIDER: S-EPMC7948459 | biostudies-literature | 2021 Jan-Jun

REPOSITORIES: biostudies-literature