Membrane-Bound Enzymes and Intramembrane-Cleaving Proteases

Special thanks to Robert Nakamoto (University of Virginia)

For more information on the topic, Jochen Zimmer of the University of Virginia will be Chairing the Symposium called “Catalysis in the Membrane” during the 2015 Biophysical Society’s 59th Annual meeting being held in Baltimore, Maryland, February 7-11.    

Digging deeper into science allows scientists to have the ability to follow where the science or biology takes them to answer new questions from different disciplines. 

Scientific training has historically produced generations of specialists. However, in the modern era, the readily applicable questions have been answered. The increase in complexity of the remaining questions are such that multiple approaches are required. This leads to convergence between techniques and the rise of generalists who employee multiple, different approaches to solve biological questions.  

This was never more evident than with intramembrane-cleaving proteases. Enzymes with active sites embedded in the cell membrane were originally thought not to exist(1). A reasonable question would be, “How could proteases, which require water to hydrolyze their targets, function inside a lipid bilayer that is protected from the aqueous environment?”

Probing the question further and using a multi-disciplinary approach, researchers were guided into new areas of study. Starting from vastly different points such as cholesterol homeostasis, Alzheimer's disease, and developmental genetics, scientists continued to dig deeper and arrived at membrane proteins. Following where the biology took them, it resulted in the discovery of intramembrane-cleaving proteases(2)   

Below, we have highlighted some of the recent work which has solved structures of membrane-bound enzymes and intramembrane-cleaving proteases.


Pryor, Edward, E., Jr., Horanyi, Peter, S., Clark, Kathleen M., Fedoriw, Nadia, Connelly, Sara M., Koszelak-Rosenblum, Mary, Zhu, Guangyu, Malkowski, Michael G., Wiener, Michael C., and Dumont, Mark E. (2013) Science 339(6127), 1600-1604.

Li, Xiaochun, Dang, Shangyu, Yan, Chuangye, Gong, Xinqi, Wang, Jiawei, and Shi, Yigong (2013) Nature 493, 56-61.

Morgan, Jacob L. W., Strumillo, Joanna, and Zimmer, Jochen (2013) Nature 493, 181-186. 

Quigley, Andrew, Dong, Yin Yao, Pike, Ashley C. W., Dong, Liang, Shrestha, Leela, Berridge, Georgina, Stansfeld, Phillip J., Sansom, Mark S. P., Edwards, Aled M., Bountra, Chas, von Delft, Frank, Bullock, Alex N., Burgess-Brown, Nicola A., and Carpenter, Elisabeth P. (2013) Science 339(6127) 1604-1607.

  •  Three dimensional structure of human gamma-secretase 

Lu, Peilong; Bai, Xiao-chen; Xie, Tian; Yan, Changye; Sun, Lingfeng; Yang, Guanghui; Zhao, Yanyu; Zhou, Rui; Scheres, Sjors H. W.; Shi, Yigong; (2014) Nature (512) 166-172.

Detergents are often vital to this kind of membrane protein work. Detergents used to solve the above structures were:


Anatrace, the leader in detergents for membrane protein work


  1. Rawson, R. B. et al. Complementation cloning of S2P, a gene encoding a putative metalloprotease required for intramembrane cleavage of SREBPs. (1997) Mol. Cell 1, 47–57.

This paper presents the first identification of an I-CLiP.

  1. Urban, S. Mechanisms and cellular functions of intramembrane proteases. (2013) Biochim Biophys Acta. 1828(12), 2797-2800.