There is growing evidence indicating that membrane proteins can be cleaved within the plane of the membrane. Such cleavage liberates cytoplasmic or lumenal/extracellular fragments of transmembrane precursor proteins and allows these fragments to function at a new location. This mechanism, termed regulated intramembrane proteolysis (Rip), influences processes as diverse as cellular differentiation, lipid metabolism, and the response to unfolded proteins.
I was among the first to propose such a signal transduction mechanism. My research was focused on the regulated intramembrane proteolysis mediated by Site-2 protease (S2P). Together with other scientists in the Brown/Goldstein lab, I identified two membrane-bound transcription factors, SREBP and ATF6, as the Rip substrates for S2P. A model explaining the cleavage mechanism of S2P was built on my finding that helix-breaking amino acids in the transmembrane domain are required for the cleavage mediated by S2P.
Ye, J., Brown, M.S., Goldstein, J.L. “Regulated Intramembrane Proteolysis” Encyclopedia of Biochemistry. 665-671 (2004).
Brown, M.S., Ye, J., Rawson, R.B., Goldstein, J.L. “Regulated intramembrane proteolysis: a control mechanism conserved from bacteria to humans.” Cell 100: 391-398 (2000).
Ye, J., Rawson, R.B., Ryutaro, K., Chen, X., Davé, U.P., Prywes, R., Brown, M.S., Goldstein, J.L. “ER Stress Induces Cleavage of Membrane-Bound ATF6 by the Same Proteases that Process SREBPs” Molecular Cell 6: 1355-1364 (2000).
Ye, J., Davé, U.P., Goldstein, J.L., Brown, M.S. “Asparagine-proline sequence within membrane-spanning segment of SREBP triggers intramembrane cleavage by Site-2 protease” Proceedings of the National AcademyRawson, R.B., Zelenski, N.G., Nijhawan, D., Ye, J., Sakai, J., Hasan, M.T., Chang, T.Y., Brown, M.S., Goldstein, J.L. “Complementation cloning of S2P, a gene encoding a putative metalloprotease required for intramembrane cleavage of SREBPs” Molecular Cell 1: 47-57 (1997).