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Atlas — HTT (Huntingtin)

UniProt: P42858 Gene symbol: HTT Protein: Huntingtin Organism: Homo sapiens (taxonomy ID 9606) Disease (MONDO): MONDO:0007739 — Huntington disease. OMIM: 613004 (HTT gene), 143100 (HD). Disease class: trinucleotide-repeat disorder; neurodegenerative; autosomal dominant.

Question this atlas entry answers

A neurogenetics group needs to characterise huntingtin: the polyglutamine (polyQ) tract that drives disease, the structural disorder of the N-terminus, and the lack of a directly druggable small-molecule target (the therapeutic axis is lowering HTT expression — antisense oligonucleotides, RNAi).

Tool sequence

# Tool Question
1 uniprot_get_entry("P42858") Function (huntingtin scaffold), length (~3142 aa), domain organisation.
2 uniprot_features_at_position("P42858", 18) Polyglutamine repeat region (~residues 18–36 normal).
3 uniprot_get_processing_features("P42858") Caspase cleavage sites that release the toxic N-terminal fragment.
4 uniprot_get_alphafold_confidence("P42858") pLDDT distribution; large disordered regions expected.
5 uniprot_resolve_pdb("P42858") PDB coverage of HEAT repeats; full-length is too large to crystallise.
6 uniprot_get_disease_associations("P42858") Huntington disease (MIM:143100).

Expected response shape

  • Step 2: features at the polyQ region include Compositional bias (polyQ), Region (HEAT repeat), and possibly Repeat annotations.
  • Step 3: caspase-3 cleavage at residues ~513 and ~552 should be annotated as Site features in the entry.
  • Step 4: bimodal pLDDT — HEAT repeat core in confident/very high, N-terminus and inter-repeat linkers in low/very low.
  • Step 5: structures cover individual HEAT repeats and the N-HEAT/C-HEAT subdomains; full-length structures are limited to cryo-EM at moderate resolution.

Therapeutic axis (interpretation)

  • HTT-lowering therapies (antisense oligonucleotides like tominersen; RNAi like AMT-130) target the RNA, not the protein.
  • Splice-modulating approaches alter HTT mRNA processing.
  • Small-molecule inhibition of HTT itself is not a viable axis — too large, too disordered, no druggable pocket.
  • ChEMBL bridge: HTT entries in ChEMBL primarily reference research compounds for HTT-aggregation imaging, not therapeutic small molecules.

Provenance fields

Standard envelope on every response.

Cross-references in scope

Resource Returned via
PDB Multiple HEAT-repeat segment structures.
AlphaFold DB AF-P42858-F1 full-length model (with confidence bands).
InterPro HEAT repeat signature; HTT family signature.
OMIM 143100 (Huntington disease).
ClinVar CAG-repeat sizing variants (the canonical "expansion").

Adjacent ontologies

Ontology Identifier
MONDO MONDO:0007739 (Huntington disease)
HPO HP:0002073 (chorea), HP:0000726 (dementia), many more
Orphanet ORPHA:399 (Huntington disease)

Why HTT

HTT exercises the "long, partially-disordered protein" case — showing how the AlphaFold confidence-band tool surfaces the boundary between structured (HEAT repeats) and disordered regions. It also illustrates an honest empty-set ChEMBL response: not every disease-associated protein is a small-molecule drug target, and the tool's empty-set advisory directs users to the actual therapeutic axis (HTT lowering).