{"uniprot":"Q86XJ0","gene":"CALHM3","name":"Calcium homeostasis modulator protein 3","organism":"Homo sapiens (Human)","status":"dark","length":344,"sequence":"MDKFRMLFQHFQSSSESVMNGICLLLAAVTVKLYSSFDFNCPCLVHYNALYGLGLLLTPPLALFLCGLLANRQSVVMVEEWRRPAGHRRKDPGIIRYMCSSVLQRALAAPLVWILLALLDGKCFVCAFSSSVDPEKFLDFANMTPSQVQLFLAKVPCKEDELVRDSPARKAVSRYLRCLSQAIGWSVTLLLIIAAFLARCLRPCFDQTVFLQRRYWSNYVDLEQKLFDETCCEHARDFAHRCVLHFFASMRSELQARGLRRGNAGRRLELPAVPEPPEGLDSGSGKAHLRAISSREQVDRLLSTWYSSKPPLDLAASPGLCGGGLSHRAPTLALGTRLSQHTDV","function_summary":"A human multi-pass membrane protein that assembles into homooligomeric complexes at the cell surface to modulate calcium and broader ion homeostasis. By forming a membrane-embedded platform, it likely tunes excitability in neurons and coordinates epithelial transport in the kidney collecting duct. Its mechanism centers on self-association into higher-order assemblies that create or regulate a membrane conduit, thereby coupling calcium-dependent signaling to local transport and receptor/channel microdomains at the plasma membrane.","plain_language":"CALHM3 has barely been studied. The model's best guess: A human multi-pass membrane protein that assembles into homooligomeric complexes at the cell surface to modulate calcium and broader ion homeostasis. By forming a membrane-embedded platform, it likely tunes excitability in neurons and coordinates epithelial transport in the kidney collecting duct.","uniprot_summary":"Probable homooligomer that may play a role in calcium homeostasis. May be involved in neuronal excitability and renal concentrating ability (By similarity).","go_terms":{"molecular_function":[{"id":"GO:0005515","label":"protein binding"}],"biological_process":[{"id":"GO:0051260","label":"protein homooligomerization"}],"cellular_component":[{"id":"GO:0005886","label":"plasma membrane"}]},"interpro":[{"id":"IPR029569","name":"Calcium homeostasis modulator family","type":"family","start":1,"end":314}],"reasoning":"I begin with the InterPro architecture: IPR029569 (Calcium homeostasis modulator family, residues 1–314) spans essentially the entire polypeptide, marking it as a CALHM-family membrane protein. CALHM-family signatures denote a multi-pass membrane topology that assembles into higher-order oligomers and forms aqueous pores or conduits in lipid bilayers. The full-length coverage of this family domain implies that oligomerization is intrinsic to function and that membrane-embedded assemblies govern ion and signal transduction rather than soluble catalysis.\n\nThis CALHM-family architecture causally supports a molecular function centered on multivalent protein association and assembly. The absence of catalytic motifs and the presence of a broad family signature that encodes oligomeric pore formation point to GO:0005515 protein binding as the operative molecular function: the protein binds and oligomerizes to build a membrane-resident complex that can modulate transmembrane fluxes and signaling.\n\nFrom this assembly logic, the biological process follows. CALHM-family members typically self-associate into stable rings or stacks; thus GO:0051260 protein homooligomerization is not incidental but required for function. Homooligomerization creates a gated conduit whose open probability and localization can be tuned by cellular cues, aligning with roles in neuronal excitability and epithelial transport.\n\nThe cellular component is dictated by the membrane-integrated, multi-pass nature of the architecture and the experimentally supported placement at the cell surface. The CALHM scaffold forms and resides at the GO:0005886 plasma membrane, where its oligomeric assemblies can directly influence membrane potential and receptor/channel microdomains.\n\nMechanistically, I infer that the protein forms homooligomeric pores or leak pathways whose activity modulates calcium and related ion homeostasis at the cell surface. In neurons, such assemblies can dampen or shape excitability by altering local ion flux and coupling to receptor/channel complexes; in the kidney collecting duct, they can tune epithelial transport by organizing membrane microdomains. Likely interaction partners therefore include membrane scaffolds and channel/receptor complexes that define these microdomains. Candidates include calmodulin (a canonical Ca2+-sensor that can regulate CALHM assemblies), AMPA-type glutamate receptor subunits and auxiliary proteins that set postsynaptic excitability, and epithelial transport modules such as ENaC/BSC complex components and their adaptors. Together, these associations would anchor the oligomeric CALHM platform at the plasma membrane and couple its pore-forming propensity to calcium homeostasis and signal transduction.","category":"dark","control_evaluation":null,"validation_plan":null,"structure":{"source":"AlphaFold DB","pdb":"/structures/AF-Q86XJ0.pdb","alphafold":"https://alphafold.ebi.ac.uk/entry/Q86XJ0"},"links":{"uniprot":"https://www.uniprot.org/uniprotkb/Q86XJ0/entry","atlas":"/p/Q86XJ0"},"provenance":{"model":"BioReason-Pro (ESM3 esm3-sm-open-v1)","source_list":"Pharos Tdark","note":"AI prediction, not experimentally verified"}}