The sarco/endoplasmic reticulum Ca 2+ -ATPase (SERCA) maintains cellular calcium homeostasis by actively transporting Ca 2+ from the cytoplasm to the ER lumen. Among SERCA isoforms, SERCA2b is unique in possessing a C-terminal extension (CTE) composed of an unstructured loop (L10/11), a transmembrane helix (M11), and a luminal extension tail (LE). The structure of SERCA2b has been resolved, except for the L10/11 region. While the CTE’s inhibitory role is recognized, its molecular mechanism remains unclear. Integrative structural modeling and molecular dynamics simulations revealed that L10/11, containing a short helical segment (Helix 1003 ), adopts a conformation complementary to a binding site formed by loops L8/9 and L6/7. This persistent interaction across multiple intermediates identifies L8/9-L6/7 as the native binding site for L10/11 during the transport cycle. By stabilizing conformations of SERCA2b, this interaction impedes intermediate transitions essential for Ca 2+ transport by a “Pull and block” dual mechanism. Functional studies of SERCA2b variants with disrupted L10/11 interactions further confirm its inhibitory role in the transport mechanism. We propose an autoinhibitory mechanism mediated by the CTE in SERCA2b: LE anchors M11, stabilizing its orientation to enable Helix 1003 binding between L8/9 and L6/7, which restricts central core tilting and prevents conformational transitions essential for Ca 2+ transport. If Helix 1003 binding is disrupted (e.g., by mutations), inhibitory control shifts to the interactions between L10/11 and the phosphorylation domain, maintaining partial suppression of activity. Importantly, L10/11 emerges as a therapeutic target for Darier’s disease, a SERCA2b-linked disorder, offering a strategy to modulate its activity in pathological contexts.
Ma et al. (Sun,) studied this question.