Shearer Alexander G, Hampton Randolph Y
Department of Biology, UCSD Division of Biological Sciences, Section of Cell and Molecular Biology, La Jolla, CA 92093, USA.
EMBO J. 2005 Jan 12;24(1):149-59. doi: 10.1038/sj.emboj.7600498. Epub 2005 Jan 6.
Cellular quality control requires recognition of common features of misfolding, and so is not typically associated with the specific targeting of individual proteins. However, physiologically regulated degradation of yeast HMG-CoA reductase (Hmg2p) occurs by the HRD endoplasmic reticulum quality control pathway, implying that Hmg2p undergoes a regulated transition to a quality control substrate in response to a sterol pathway molecule. Using in vitro structural assays, we now show that the pathway derivative farnesol causes Hmg2p to undergo a change to a less folded structure. The effect is reversible, biologically relevant by numerous criteria, highly specific for farnesol structure, and requires an intact Hmg2p sterol-sensing domain. This represents a distinct lipid-sensing function for this highly conserved motif that suggests novel approaches to cholesterol management. More generally, our observation of reversible small-molecule-mediated misfolding may herald numerous examples of regulated quality control to be discovered in biology or applied in the clinic.
细胞质量控制需要识别错误折叠的共同特征，因此通常与单个蛋白质的特异性靶向无关。然而，酵母HMG-CoA还原酶（Hmg2p）的生理调节性降解是通过HRD内质网质量控制途径发生的，这意味着Hmg2p会响应固醇途径分子而经历向质量控制底物的调节性转变。通过体外结构分析，我们现在表明途径衍生物法尼醇会使Hmg2p转变为折叠程度较低的结构。这种效应是可逆的，在许多标准下具有生物学相关性，对法尼醇结构具有高度特异性，并且需要完整的Hmg2p固醇感应结构域。这代表了这个高度保守基序的一种独特的脂质感应功能，提示了胆固醇管理的新方法。更普遍地说，我们对可逆的小分子介导的错误折叠的观察可能预示着在生物学中会发现或在临床上应用的许多调节性质量控制的例子。
