{"uniprot":"Q6ZSJ9","gene":"SHISA6","name":"Protein shisa-6","organism":"Homo sapiens (Human)","status":"dark","length":500,"sequence":"MALRRLLLLLLLSLESLDLLPSVHGARGRAANRTLSAGGAAVGGRRAGGALARGGRELNGTARAPGIPEAGSRRGQPAAAVAAAASAAVTYETCWGYYDVSGQYDKEFECNNSESGYLYCCGTCYYRFCCKKRHEKLDQRQCTNYQSPVWVQTPSTKVVSPGPENKYDPEKDKTNFTVYITCGVIAFVIVAGVFAKVSYDKAHRPPREMNIHRALADILRQQGPIPIAHCERETISAIDTSPKENTPVRSSSKNHYTPVRTAKQTPEKPRMNNILTSATEPYDLSFSRSFQNLAHLPPSYESAVKTNPSKYSSLKRLTDKEADEYYMRRRHLPDLAARGTLPLNVIQMSQQKPLPRERPRRPIRAMSQDRVLSPDRGLPDEFSMPYDRILSDEQLLSTERLHSQDPLLSPERTAFPEQSLSRAISHTDVFVSTPVLDRYRMSKMHSHPSASNNSYATLGQSQTAAKRHAFASRRHNTVEQLHYIPGHHTCYTASKTEVTV","function_summary":"A single-pass membrane regulator at excitatory synapses that uses an extracellular Shisa module and a short cytosolic tail to assemble and tune postsynaptic receptor complexes. By binding and organizing AMPA receptor assemblies within the postsynaptic density membrane, it modulates excitatory synaptic transmission and adjusts AMPA receptor activity through effects on complex assembly, trafficking, and retention at glutamatergic synapses.","plain_language":"SHISA6 has barely been studied. The model's best guess: A single-pass membrane regulator at excitatory synapses that uses an extracellular Shisa module and a short cytosolic tail to assemble and tune postsynaptic receptor complexes. By binding and organizing AMPA receptor assemblies within the postsynaptic density membrane, it modulates excitatory synaptic transmission and adjusts AMPA receptor activity through effects on complex assembly, trafficking, and retention at glutamatergic synapses.","uniprot_summary":"Involved in the regulation of synaptic transmission.","go_terms":{"molecular_function":[{"id":"GO:0005515","label":"protein binding"}],"biological_process":[{"id":"GO:0050804","label":"modulation of chemical synaptic transmission"},{"id":"GO:2000311","label":"regulation of AMPA receptor activity"}],"cellular_component":[{"id":"GO:0098978","label":"glutamatergic synapse"},{"id":"GO:0098839","label":"postsynaptic density membrane"},{"id":"GO:0032281","label":"AMPA glutamate receptor complex"}]},"interpro":[{"id":"IPR053891","name":"Shisa, N-terminal domain","type":"domain","start":92,"end":144},{"id":"IPR026910","name":"Shisa","type":"family","start":4,"end":500}],"reasoning":"I begin with the InterPro architecture. The polypeptide carries IPR053891 (Shisa, N-terminal domain, residues 92–144) embedded within a larger IPR026910 (Shisa family, residues 4–500) envelope. Shisa-family proteins are single-pass type I membrane modulators whose luminal/extracellular N-terminal module and a short cytosolic tail orchestrate protein–protein interactions and trafficking of membrane signaling assemblies. The discrete Shisa N-terminal domain at 92–144 provides a structured extracellular scaffold that stabilizes or tunes receptor complexes, while the broader Shisa-family signature across 4–500 indicates a conserved membrane-anchored regulatory framework rather than enzymatic chemistry. This architecture dictates a non-catalytic, interaction-centric role that relies on multivalent binding—consistent with GO:0005515 protein binding as the molecular function.\n\nFrom this binding-centric membrane scaffold, the causal next step is modulation of synaptic receptor systems. The Shisa N-terminal domain is positioned to influence postsynaptic receptor assemblies by altering their maturation, surface stability, and coupling to intracellular adaptors. Such modulation directly shapes synaptic throughput, aligning with GO:0050804 modulation of chemical synaptic transmission. The explicit linkage to AMPA receptor systems is supported by the Shisa family’s known specialization in excitatory synapses and by the requirement for precise tuning of glutamatergic signaling; thus the architecture naturally supports GO:2000311 regulation of AMPA receptor activity.\n\nCellular placement follows from both topology and function. A single-pass type I membrane layout places the N-terminal Shisa domain extracellularly and the C-terminal tail cytosolic, a configuration that anchors in excitatory postsynaptic membranes. The functional footprint at glutamatergic sites predicts accumulation at the GO:0098978 glutamatergic synapse and specifically the GO:0098839 postsynaptic density membrane, where AMPA receptor complexes concentrate. This is reinforced by the explicit association with the GO:0032281 AMPA glutamate receptor complex, which situates the protein at the core of postsynaptic signaling hubs.\n\nMechanistically, the Shisa N-terminal domain likely stabilizes or edits the assembly and gating behavior of AMPA receptor complexes, while the cytosolic tail recruits postsynaptic adaptors to control receptor trafficking and retention. By constraining receptor availability and coupling to downstream pathways, the protein can dampen or fine-tune synaptic gain. I therefore hypothesize that it forms transient complexes with AMPA receptor subunits and their auxiliary factors, and with postsynaptic scaffolds that govern receptor clustering and endocytic recycling. This ensemble of interactions provides a coherent route from sequence-encoded binding capacity to precise regulation of excitatory synaptic transmission at the postsynaptic density membrane.","category":"dark","control_evaluation":null,"validation_plan":null,"structure":{"source":"AlphaFold DB","pdb":"/structures/AF-Q6ZSJ9.pdb","alphafold":"https://alphafold.ebi.ac.uk/entry/Q6ZSJ9"},"links":{"uniprot":"https://www.uniprot.org/uniprotkb/Q6ZSJ9/entry","atlas":"/p/Q6ZSJ9"},"provenance":{"model":"BioReason-Pro (ESM3 esm3-sm-open-v1)","source_list":"Pharos Tdark","note":"AI prediction, not experimentally verified"}}