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  The membrane anchor of the transcriptional activator SREBP is characterized by intrinsic conformational flexibility.

Linser, R., Salvi, N., Briones, R., Rovo, P., de Groot, B. L., & Wagner, G. (2015). The membrane anchor of the transcriptional activator SREBP is characterized by intrinsic conformational flexibility. Proceedings of the National Academy of Sciences of the United States of America, 112(40), 12390-12395. doi:10.1073/pnas.1513782112.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0028-4D4C-B Version Permalink: http://hdl.handle.net/11858/00-001M-0000-002A-1C14-0
Genre: Journal Article

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 Creators:
Linser, R.1, Author              
Salvi, N., Author
Briones, R.2, Author              
Rovo, P.1, Author              
de Groot, B. L.2, Author              
Wagner, G., Author
Affiliations:
1Research Group of Solid-State NMR-2, MPI for Biophysical Chemistry, Max Planck Society, ou_1950286              
2Research Group of Computational Biomolecular Dynamics, MPI for biophysical chemistry, Max Planck Society, ou_578573              

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Free keywords: SREBP; cancer; cellular lipid homeostasis; membrane proteins; regulated intramembrane proteolysis
 Abstract: Regulated intramembrane proteolysis (RIP) is a conserved mechanism crucial for numerous cellular processes, including signaling, transcriptional regulation, axon guidance, cell adhesion, cellular stress responses, and transmembrane protein fragment degradation. Importantly, it is relevant in various diseases including Alzheimer's disease, cardiovascular diseases, and cancers. Even though a number of structures of different intramembrane proteases have been solved recently, fundamental questions concerning mechanistic underpinnings of RIP and therapeutic interventions remain. In particular, this includes substrate recognition, what properties render a given substrate amenable for RIP, and how the lipid environment affects the substrate cleavage. Members of the sterol regulatory element-binding protein (SREBP) family of transcription factors are critical regulators of genes involved in cholesterol/lipid homeostasis. After site-1 protease cleavage of the inactive SREBP transmembrane precursor protein, RIP of the anchor intermediate by site-2 protease generates the mature transcription factor. In this work, we have investigated the labile anchor intermediate of SREBP-1 using NMR spectroscopy. Surprisingly, NMR chemical shifts, site-resolved solvent exposure, and relaxation studies show that the cleavage site of the lipid-signaling protein intermediate bears rigid α-helical topology. An evolutionary conserved motif, by contrast, interrupts the secondary structure ∼9-10 residues C-terminal of the scissile bond and acts as an inducer of conformational flexibility within the carboxyl-terminal transmembrane region. These results are consistent with molecular dynamics simulations. Topology, stability, and site-resolved dynamics data suggest that the cleavage of the α-helical substrate in the case of RIP may be associated with a hinge motion triggered by the molecular environment.

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Language(s): eng - English
 Dates: 2015-09-21
 Publication Status: Published online
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 Rev. Method: Peer
 Identifiers: DOI: 10.1073/pnas.1513782112
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Title: Proceedings of the National Academy of Sciences of the United States of America
Source Genre: Journal
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Pages: - Volume / Issue: 112 (40) Sequence Number: - Start / End Page: 12390 - 12395 Identifier: ISSN: 0027-8424