8BAN

Secretagogin (mouse) in complex with its target peptide from SNAP-25

Summary for 8BAN

• Entry DOI: 10.2210/pdb8ban/pdb
• Descriptor: Green fluorescent protein,Synaptosomal-associated protein 25, Secretagogin, CALCIUM ION, ... (4 entities in total)
• Functional Keywords: calcium-dependent, protein complex, peptide binding protein
• Biological source: Aequorea victoria; More
• Total number of polymer chains: 4
• Total formula weight: 122663.34

Authors

Schnell, R.,Szodorai, E. (deposition date: 2022-10-11, release date: 2024-04-03, Last modification date: 2024-10-09)

Primary citation

Szodorai, E.,Hevesi, Z.,Wagner, L.,Hokfelt, T.G.M.,Harkany, T.,Schnell, R.
A hydrophobic groove in secretagogin allows for alternate interactions with SNAP-25 and syntaxin-4 in endocrine tissues.
Proc.Natl.Acad.Sci.USA, 121:e2309211121-e2309211121, 2024

PubMed Abstract: Vesicular release of neurotransmitters and hormones relies on the dynamic assembly of the exocytosis/trans-SNARE complex through sequential interactions of synaptobrevins, syntaxins, and SNAP-25. Despite SNARE-mediated release being fundamental for intercellular communication in all excitable tissues, the role of auxiliary proteins modulating the import of reserve vesicles to the active zone, and thus, scaling repetitive exocytosis remains less explored. Secretagogin is a Ca-sensor protein with SNAP-25 being its only known interacting partner. SNAP-25 anchors readily releasable vesicles within the active zone, thus being instrumental for 1st phase release. However, genetic deletion of secretagogin impedes 2nd phase release instead, calling for the existence of alternative protein-protein interactions. Here, we screened the secretagogin interactome in the brain and pancreas, and found syntaxin-4 grossly overrepresented. Ca-loaded secretagogin interacted with syntaxin-4 at nanomolar affinity and 1:1 stoichiometry. Crystal structures of the protein complexes revealed a hydrophobic groove in secretagogin for the binding of syntaxin-4. This groove was also used to bind SNAP-25. In mixtures of equimolar recombinant proteins, SNAP-25 was sequestered by secretagogin in competition with syntaxin-4. K differences suggested that secretagogin could shape unidirectional vesicle movement by sequential interactions, a hypothesis supported by in vitro biological data. This mechanism could facilitate the movement of transport vesicles toward release sites, particularly in the endocrine pancreas where secretagogin, SNAP-25, and syntaxin-4 coexist in both α- and β-cells. Thus, secretagogin could modulate the pace and fidelity of vesicular hormone release by differential protein interactions.

PubMed: 38593081
DOI: 10.1073/pnas.2309211121

Experimental method

X-RAY DIFFRACTION (2.35 Å)