IRE1 alpha (Inositol-requiring enzyme 1 alpha), an endoplasmic reticulum (ER)-resident sensor for mammalian unfolded protein response, is a type I transmembrane protein which has a bifunctional enzyme containing kinase and RNase domains. Although the luminal domain and cytosolic domain of IRE1 alpha are thought to play crucial roles in regulating the protein activity, no functional and structural studies of the transmembrane domain exist thus far. Herein, using CD spectroscopy, we report that the transmembrane domain of the IRE1 alpha is alpha-helical in a membrane-like environment. In addition, SDS-PAGE and FRET analyses support that the transmembrane domain forms oligomers in SDS micelles. Thus, the study would provide insights into how the transmembrane domain plays a role in regulating the IRE1 alpha protein activity. (C) 2012 Elsevier Inc. All rights reserved.