Mallostery: Ligand‐dependent Misfolding as a Strategy for Protein Regulation

Abstract

Protein quality control is an essential set of processes that allow cells to detect, manage, and destroy misfolded and otherwise aberrant proteins. A substantial component of protein quality control involves the selective destruction of misfolded proteins by the ubiquitin proteasome system. Despite the broad range of substrates subject to quality control destruction, these pathways nevertheless show striking specificity for misfolded versions of otherwise stable proteins. This high selectivity can be exploited to regulate the levels of normal proteins through ligand‐mediated, reversible misfolding. This misfolding appears to be a variant of allosteric control that, instead of causing a change in enzyme function, causes a change in enzyme folding to allow recognition and destruction on a contingency basis. This talk will describe an example of such regulated misfolding involved in the control of the sterol synthesizing mevalonate pathway in yeast.HMG‐CoA Reductase (HMGR) is a rate limiting enzyme of the sterol pathway that undergoes regulated degradation as a mechanism of feedback regulation. In yeast, degradation of the HMGR isozyme Hmg2 is keyed to levels of the 20‐carbon isoprenoid geranylgeranyl pyrophosphate (GGPP). When GGPP levels are high, Hmg2 is efficiently degraded by the HRD pathway, which is a major and highly conserved pathway of quality control in the ER known as ER‐associated degradation (ERAD).We have shown that GGPP causes reversible misfolding of Hmg2 that promotes HRD dependent degradation. GGPP‐regulated Hmg2 misfolding shows remarkable similarities to allosteric regulation. GGPP action on Hmg2 is reversible and highly potent, occurring in the mid‐nanomolar range. GGPP's effects are highly specific for its structure, and its effects on Hmg2 can be antagonized both in vivo and in vitro by a related molecule. These features point to a high potency, ligand‐mediated effect on Hmg2 structure. Consistent with this, Hmg2 exists as a multimer, and unregulated Hmg2 variants show classic “toxic subunit” behavior on the regulation of wild‐type Hmg2. Finally, these effects are antagonized by chemical chaperones, demonstrating that the transition caused by GGPP is consistent with misfolding. Accordingly we call this type of regulation “mallostery” to include the ideas of misfolding and allostery in a single term.When viewed through the lens of mallostery, it appears that a number of highly diverse regulatory situations employ similar molecular tactics. Although the generality remains to be discovered, the broadest possibility is for the design of “mallosteric drugs” that specifically program the destruction of desired targets for clinical or basic scientific benefit.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.