2026-10-14T15:42:12Z https://api.figshare.com/v2/oai

oai:figshare.com:article/33669037 2026-09-12T15:29:36Z category_1 category_4 category_915 category_7 category_14 category_15 category_19 category_873 category_135 portal_63 item_type_3 month_year_09_2026

Pathway-Dependent Energetics of SLC15A4–TASL Engagement: Single-Protomer Switching and Dimer-Interface Remodeling Xiaoyu Zhao (197804) Danyang Xiong (12962632) Feng Gao (3548) Xiao He (223527) Biophysics Biochemistry Physical Sciences not elsewhere classified Medicine Molecular Biology Neuroscience Pharmacology Chemical Sciences not elsewhere classified Computational Biology side interfacial stabilization reshaping electrostatic determinants quantitative energetic rationale modeled asymmetric intermediate mfs helical bundles leaving assembly bottlenecks key cationic sites inhibitor limits access inhibitor interception without embedded signalosome assembly computational energetic framework centered interfacial scaffold energy rise near competitive cavity occupation interface remodeling membrane support irf5 signaling rapid contact formation luminal hydrophobic packing reduced interface persistence pronounced apparent free prescribed tasl entry prescribed insertion pathway protomer interface geometry resting apo dimer luminal interface weakening slc15a4 recruits tasl energy cost along energy cost interface persistence slc15a4 maintained energy profiles central cavity apo state protomer switching protomer switch yet short static structures results suggest potentially contributing permissive state oligomeric interfaces multivalent hydrogen lipid microenvironment lipid coupling directional anchoring dependent energetics conformational selection altered cross Membrane-embedded signalosome assembly is co-gated by conformational selection, oligomeric interfaces, and the lipid microenvironment, yet short-lived, tightly coupled intermediate states are hard to infer from static structures. SLC15A4 recruits TASL to support IRF5 signaling, but available structures largely capture distinct conformational endpoints, leaving assembly bottlenecks, interface/lipid coupling, and inhibitor interception without a quantitative energetic rationale. Here, we developed a computational energetic framework connecting the resting apo dimer to a TASL-permissive state. In the apo state, SLC15A4 maintained a persistent dimeric arrangement organized around a TM9/TM12-centered interfacial scaffold, while the interfacial cholesterol molecules maintained persistent contacts with the interface; luminal hydrophobic packing and a multivalent hydrogen-bond network around N428 were associated with interface persistence, while the dimer retained characteristic coupled motions of MFS helical bundles. Along the prescribed insertion pathway, TASL exhibited a pronounced apparent free-energy rise near the pocket, accompanied by rapid contact formation and a single-protomer switch from luminal-open to cytosolic-open, yielding a modeled asymmetric intermediate with altered cross-protomer interface geometry. TASL was stabilized by directional anchoring at a few key cationic sites. Pathway-dependent free-energy profiles further indicated that TASL engagement relaxed luminal-side interfacial stabilization and lowered the free-energy cost of inter-subunit separation without compromising pocket binding, potentially contributing to the formation of a signaling-competent SLC15A4–TASL module. Finally, our results suggest that an inhibitor limits access to the TASL-permissive state by locking the luminal-open conformation and occupying the central cavity, increasing the free-energy cost along the prescribed TASL entry and reshaping electrostatic determinants. Together, these results connect experimentally resolved structural states through a computational energetic framework in which TASL-associated single-protomer switching may couple to luminal interface weakening and reduced interface persistence, motivating therapeutic strategies targeting the SLC15A4–TASL–IRF5 axis via conformational locking and competitive cavity occupation. 2026-09-12T00:00:00Z Dataset Dataset 10.1021/acs.jctc.6c01438.s002 https://figshare.com/articles/dataset/Pathway-Dependent_Energetics_of_SLC15A4_TASL_Engagement_Single-Protomer_Switching_and_Dimer-Interface_Remodeling/33669037 CC BY-NC 4.0