Understanding intramembrane proteolysis: from protein dynamics to reaction kinetics.
Intramembrane proteolysis - cleavage of proteins within the plane of a membrane - is a widespread phenomenon that can contribute to the functional activation of substrates and is involved in several diseases. Although different families of intramembrane proteases have been discovered and characterized, we currently do not know how these enzymes discriminate between substrates and non-substrates, how site-specific cleavage is achieved, or which factors determine the rate of proteolysis. Focusing on γ-secretase and rhomboid proteases, we argue that answers to these questions may emerge from connecting experimental readouts, such as reaction kinetics and the determination of cleavage sites, to the structures and the conformational dynamics of substrates and enzymes.
Technische Universität München, Lehrstuhl Chemie der Biopolymere, Weihenstephaner Berg 3, 85354 Freising, and Munich Center for Integrated Protein Science (CIMPS(M)), Germany. Electronic address: langosch@tum.de.
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Langosch
Fakultät für Physik E14, Technische Universität München, Maximus-von-Imhof-Forum 4, 85354 Freising, Germany.
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Scharnagl
Ludwig-Maximilians-University Munich, Metabolic Biochemistry and DZNE (German Center for Neurodegenerative Diseases), Munich, Germany.
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Steiner
Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH), Deutsches Krebsforschungszentrum (DKFZ)-ZMBH Allianz, Im Neuenheimer Feld 282, 69120 Heidelberg, Germany.
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Lemberg
D053829:Amyloid Precursor Protein Secretases / Q000737:chemistry; D002462:Cell Membrane / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008565:Membrane Proteins / Q000737:chemistry* / Q000378:metabolism; D010447:Peptide Hydrolases / Q000737:chemistry / Q000378:metabolism*; D059748:Proteolysis
D008565:Membrane Proteins; D053829:Amyloid Precursor Protein Secretases; D010447:Peptide Hydrolases
conformational dynamics; intramembrane proteolysis/protease; presenilin; rhomboid; transmembrane helix; γ-secretase