{"uniprot":"Q96II8","gene":"LRCH3","name":"Leucine-rich repeat and calponin homology domain-containing protein 3","organism":"Homo sapiens (Human)","status":"dark","length":777,"sequence":"MAAAGLVAVAAAAEYSGTVASGGNLPGVHCGPSSGAGPGFGPGSWSRSLDRALEEAAVTGVLSLSGRKLREFPRGAANHDLTDTTRADLSRNRLSEIPIEACHFVSLENLNLYQNCIRYIPEAILNLQALTFLNISRNQLSTLPVHLCNLPLKVLIASNNKLVSLPEEIGHLRHLMELDVSCNEIQTIPSQIGNLEALRDLNVRRNHLVHLPEELAELPLIRLDFSCNKITTIPVCYRNLRHLQTITLDNNPLQSPPAQICIKGKVHIFKYLNIQACKIAPDLPDYDRRPLGFGSCHEELYSSRPYGALDSGFNSVDSGDKRWSGNEPTDEFSDLPLRVAEITKEQRLRRESQYQENRGSLVVTNGGVEHDLDQIDYIDSCTAEEEEAEVRQPKGPDPDSLSSQFMAYIEQRRISHEGSPVKPVAIREFQKTEDMRRYLHQNRVPAEPSSLLSLSASHNQLSHTDLELHQRREQLVERTRREAQLAALQYEEEKIRTKQIQRDAVLDFVKQKASQSPQKQHPLLDGVDGECPFPSRRSQHTDDSALCMSLSGLNQVGCAATLPHSSAFTPLKSDDRPNALLSSPATETVHHSPAYSFPAAIQRNQPQRPESFLFRAGVRAETNKGHASPLPPSAAPTTDSTDSITGQNSRQREEELELIDQLRKHIEYRLKVSLPCDLGAALTDGVVLCHLANHVRPRSVPSIHVPSPAVPKLTMAKCRRNVENFLEACRKIGVPQEQLCLPLHILEEKGLSQVAVTVQALLELAPPKQQQHQLSAV","function_summary":"A cytoplasmic adaptor that combines an N-terminal leucine-rich repeat scaffold with a C-terminal calponin-homology module to assemble and position cytoskeletal complexes. The LRR array recruits partner proteins, while the calponin-homology fold anchors assemblies to actin-rich regions, thereby guiding the organization of septin-based structures. Operating as a soluble scaffold in the cytosol, it likely coordinates the assembly and maintenance of filament systems by concentrating septins and associated factors at appropriate cortical sites.","plain_language":"LRCH3 has barely been studied. The model's best guess: A cytoplasmic adaptor that combines an N-terminal leucine-rich repeat scaffold with a C-terminal calponin-homology module to assemble and position cytoskeletal complexes. The LRR array recruits partner proteins, while the calponin-homology fold anchors assemblies to actin-rich regions, thereby guiding the organization of septin-based structures.","uniprot_summary":"May be involved in cytoskeletal organization.","go_terms":{"molecular_function":[{"id":"GO:0005515","label":"protein binding"}],"biological_process":[{"id":"GO:0032185","label":"septin cytoskeleton organization"}],"cellular_component":[{"id":"GO:0005829","label":"cytosol"}]},"interpro":[{"id":"IPR032675","name":"Leucine-rich repeat domain superfamily","type":"homologous_superfamily","start":46,"end":285},{"id":"IPR036872","name":"CH domain superfamily","type":"homologous_superfamily","start":649,"end":776},{"id":"IPR001715","name":"Calponin homology domain","type":"domain","start":652,"end":765},{"id":"IPR050216","name":"Leucine-rich repeat domain-containing protein","type":"family","start":49,"end":494},{"id":"IPR001611","name":"Leucine-rich repeat","type":"repeat","start":88,"end":140},{"id":"IPR003591","name":"Leucine-rich repeat, typical subtype","type":"repeat","start":104,"end":126},{"id":"IPR003591","name":"Leucine-rich repeat, typical subtype","type":"repeat","start":127,"end":150},{"id":"IPR001611","name":"Leucine-rich repeat","type":"repeat","start":152,"end":208},{"id":"IPR003591","name":"Leucine-rich repeat, typical subtype","type":"repeat","start":172,"end":194},{"id":"IPR003591","name":"Leucine-rich repeat, typical subtype","type":"repeat","start":195,"end":218},{"id":"IPR003591","name":"Leucine-rich repeat, typical subtype","type":"repeat","start":240,"end":263}],"reasoning":"I begin with the domain architecture. The N-terminal half is dominated by a leucine-rich repeat (LRR) scaffold: IPR032675 (Leucine-rich repeat domain superfamily, residues 46–285) and IPR050216 (Leucine-rich repeat domain-containing protein family, residues 49–494) define a curved solenoid platform optimized for avid, selective protein–protein interactions. This platform is reinforced by multiple tandem LRR units—IPR001611 (Leucine-rich repeat, residues 88–140), IPR003591 typical LRR repeats at 104–126, 127–150, 172–194, 195–218, and 240–263—that collectively create a continuous binding surface. Such an N-terminal LRR array causes high-capacity scaffolding and substrate capture, a hallmark of cytoskeletal adaptors.\n\nThe C-terminal half switches to an actin-binding module: IPR036872 (CH domain superfamily, residues 649–776) and its core IPR001715 (Calponin homology domain, residues 652–765) specify a calponin-homology fold that binds actin and actin-associated assemblies. The ordered architecture—LRR scaffold followed by a CH domain—creates a bipartite adaptor: the LRR region recruits partners, while the CH domain anchors to actin-rich structures. This arrangement causally supports GO:0005515 protein binding as the molecular function, with the LRR array supplying multivalent affinity and the CH domain conferring cytoskeletal engagement.\n\nFrom this molecular toolkit, the biological role follows. A CH-anchored scaffold that concentrates partners is well-suited to organize higher-order cytoskeletal systems. The explicit coupling of an LRR assembly platform to an actin-binding CH domain provides a mechanism to position and stabilize septin structures—filamentous assemblies that template actin and membrane organization. This directly aligns with GO:0032185 septin cytoskeleton organization: the LRR array nucleates septin- and membrane-associated complexes, while the CH domain tethers the assembly to actin-rich sites where septins polymerize and cap filaments.\n\nCellular placement is consistent with soluble cytoskeletal hubs. The absence of transmembrane features and the presence of soluble interaction modules point to a cytosolic pool that dynamically associates with filament systems, matching GO:0005829 cytosol and the broader cytoplasmic designation. The experimentally observed cytoplasmic localization is therefore a natural consequence of this soluble adaptor architecture.\n\nMechanistically, I hypothesize that the LRR block captures septin hetero-oligomers and membrane-curvature proteins, concentrating them into pre-filament assemblies. The downstream CH domain then stabilizes these assemblies at actin-dense cortical regions, biasing septin filament nucleation and maintenance. Likely interaction partners include septin family members (to supply filament cores), actin and actin-binding proteins (to provide anchorage and spatial cues), and membrane-associated adaptors that sense curvature—together forming a cytosolic scaffold that choreographs septin cytoskeleton organization.","category":"dark","control_evaluation":null,"validation_plan":null,"structure":{"source":"AlphaFold DB","pdb":"/structures/AF-Q96II8.pdb","alphafold":"https://alphafold.ebi.ac.uk/entry/Q96II8"},"links":{"uniprot":"https://www.uniprot.org/uniprotkb/Q96II8/entry","atlas":"/p/Q96II8"},"provenance":{"model":"BioReason-Pro (ESM3 esm3-sm-open-v1)","source_list":"Pharos Tdark","note":"AI prediction, not experimentally verified"}}