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TitleSPRING licenses S1P-mediated cleavage of SREBP2 by displacing an inhibitory pro-domain.
Journal, issue, pagesNat Commun, Vol. 15, Issue 1, Page 5732, Year 2024
Publish dateJul 9, 2024
AuthorsSebastian Hendrix / Vincent Dartigue / Hailee Hall / Shrankhla Bawaria / Jenina Kingma / Bilkish Bajaj / Noam Zelcer / Daniel L Kober /
PubMed AbstractSite-one protease (S1P) conducts the first of two cleavage events in the Golgi to activate Sterol regulatory element binding proteins (SREBPs) and upregulate lipogenic transcription. S1P is also ...Site-one protease (S1P) conducts the first of two cleavage events in the Golgi to activate Sterol regulatory element binding proteins (SREBPs) and upregulate lipogenic transcription. S1P is also required for a wide array of additional signaling pathways. A zymogen serine protease, S1P matures through autoproteolysis of two pro-domains, with one cleavage event in the endoplasmic reticulum (ER) and the other in the Golgi. We recently identified the SREBP regulating gene, (SPRING), which enhances S1P maturation and is necessary for SREBP signaling. Here, we report the cryo-EM structures of S1P and S1P-SPRING at sub-2.5 Å resolution. SPRING activates S1P by dislodging its inhibitory pro-domain and stabilizing intra-domain contacts. Functionally, SPRING licenses S1P to cleave its cognate substrate, SREBP2. Our findings reveal an activation mechanism for S1P and provide insights into how spatial control of S1P activity underpins cholesterol homeostasis.
External linksNat Commun / PubMed:38977690 / PubMed Central
MethodsEM (single particle)
Resolution2.27 - 2.3 Å
Structure data

42639

8uw8

EMDB-42639, PDB-8uw8:
Site-one protease and SPRING
Method: EM (single particle) / Resolution: 2.3 Å

42661

8uwc

EMDB-42661, PDB-8uwc:
Site-one protease without SPRING
Method: EM (single particle) / Resolution: 2.27 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

ChemComp-CA:
Unknown entry

ChemComp-HOH:
WATER

Source
  • homo sapiens (human)
KeywordsSIGNALING PROTEIN / serine protease cholesterol metabolism zymogen activation Protein complex glycoprotein secretory pathway

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