biostudies-literatureWeninger GNIDDK NIH HHSNHLBI NIH HHSNINDS NIH HHSNIGMS NIH HHSe2400497121https://www.ebi.ac.uk/biostudies/studies/S-EPMC11228480biostudies-literatureUnknown121(27)S100A1, a small homodimeric EF-hand Ca²⁺-binding protein (~21 kDa), plays an important regulatory role in Ca²⁺ signaling pathways involved in various biological functions including Ca²⁺ cycling and contractile performance in skeletal and cardiac myocytes. One key target of the S100A1 interactome is the ryanodine receptor (RyR), a huge homotetrameric Ca²⁺ release channel (~2.3 MDa) of the sarcoplasmic reticulum. Here, we report cryoelectron microscopy structures of S100A1 bound to RyR1, the skeletal muscle isoform, in absence and presence of Ca²⁺. Ca²⁺-free apo-S100A1 binds beneath the bridging solenoid (BSol) and forms contacts with the junctional solenoid and the shell-core linker of RyR1. Upon Ca²⁺-binding, S100Proceedings of the National Academy of Sciences of the United States of AmericaStructural insights into the regulation of RyR1 by S100A1.PMC11228480R01 GM129325P01 HL164319R01 NS114570RF1 NS114570R01 DK118240R25 NS076445R01 HL145473R01 HL140934R01 HL142903T32 HL120826R25 HL156002Weninger GReiken SYuan QWronska ADridi HBrandenburg SLiu YMarks ARRiedemann GCChang AMiotto MCLehnart SETchagou CfalseStructural insights into the regulation of RyR1 by S100A1.S100A1, a small homodimeric EF-hand Ca²⁺-binding protein (~21 kDa), plays an important regulatory role in Ca²⁺ signaling pathways involved in various biological functions including Ca²⁺ cycling and contractile performance in skeletal and cardiac myocytes. One key target of the S100A1 interactome is the ryanodine receptor (RyR), a huge homotetrameric Ca²⁺ release channel (~2.3 MDa) of the sarcoplasmic reticulum. Here, we report cryoelectron microscopy structures of S100A1 bound to RyR1, the skeletal muscle isoform, in absence and presence of Ca²⁺. Ca²⁺-free apo-S100A1 binds beneath the bridging solenoid (BSol) and forms contacts with the junctional solenoid and the shell-core linker of RyR1. Upon Ca²⁺-binding, S1002024-01-01T00:00:00Z2024 Jul2026-06-01T13:36:00.158Z2025-04-04T11:24:08.808ZS-EPMC112284803891701010.1073/pnas.2400497121