TBX5 (human, Q99593) review notes

Automated deep research was unavailable for this session (falcon 402, OpenAI 401), so these
notes were compiled manually from cached publications (publications/PMID_*.md), the UniProt
record and PubMed searches. Most cached papers are abstract-only.

Identity and structure

• T-box transcription factor, 518 aa; T-box DNA-binding domain residues 58-238 (UniProt FT
  DNA_BIND, PROSITE PRU00201; structure PMID:26926761). PANTHER PTHR11267:SF28
  (T-BOX TRANSCRIPTION FACTOR TBX5), TBX2/3/4/5 subfamily.
• Binds T-box elements (TBE, consensus AGGTGTGA). EMSA with a synthetic site
  PMID:12499378.
• Crystal structure of TBX5 + NKX2-5 DNA-binding domains on a 19-bp NPPA target
  PMID:26926761; also a TBX5 homodimer.
• Two cooperating NLSs PMID:14519429.
• Acetylation of K339 by KAT2A/KAT2B potentiates activity and nuclear retention
  PMID:29174768.
• Nucleocytoplasmic shuttling controlled by the PDZ-LIM protein PDLIM7/LMP4, which tethers TBX5 to
  actin and represses its activity [PMID:16880269 "In the presence of LMP4, Tbx5 shuttles dynamically between the nucleus and cytoplasm"; "LMP4 acts as a repressor of Tbx5 activity"]; zebrafish
  Pdlim7 balance of Tbx5 activity at the AV boundary PMID:19895804.

Molecular function: sequence-specific Pol II activator with cardiac TF partners

• NKX2-5: Y2H with Nkx2-5 bait isolated Tbx5; the two bind the Nppa promoter in tandem and synergise
  PMID:11431700.
  HOS missense mutants lose NKX2-5 interaction and synergy PMID:12499378.
  ANF and Cx40 (Gja5) promoters are cooperatively activated with Nkx2-5 and are dosage-sensitive targets PMID:11572777.
  Consistent with the NKX2-5 review in this repo, which MODIFYs TBX5 protein-binding rows to GO:0061629.
• GATA4: physical interaction disrupted by GATA4 G296S and by HOS TBX5 missense mutations
  PMID:12845333; GATA4 N285S
  also disrupts it PMID:24000169.
• MEF2C: direct interaction through DNA-binding domains, synergistic MYH6 activation PMID:19204083.
• SALL4: Tbx5 regulates Sall4 and the two interact positively and negatively in forelimb and heart
  PMID:16380715.
• Coactivators TAZ (WWTR1) and YAP1 PMID:16332960;
  in beta-catenin-driven cancer cells a beta-catenin-YAP1-TBX5 complex activates BCL2L1/BIRC5 PMID:23245941.
• KAT2A/KAT2B bind and acetylate TBX5 PMID:29174768.

Biological roles

• Holt-Oram syndrome (heart-hand): TBX5 haploinsufficiency [PMID:8988164; PMID:8988165 "We conclude that TBX5 is critical for limb and heart development and suggest that haploinsufficiency of TBX5 causes Holt-Oram syndrome"].
  Strict criteria require preaxial radial-ray defects PMID:16183809.
• Forelimb: mouse Tbx5 null embryos lack forelimb buds; Tbx5 directly activates Fgf10
  PMID:12490567;
  conditional deletion confirms requirement for bud formation and outgrowth PMID:12736217.
• Heart: Tbx5 del/del causes posterior (atrial/sinoatrial) hypoplasia; haploinsufficiency reduces
  ANF and Cx40 PMID:11572777. Ventricular septation set by a Tbx5 gradient PMID:19727199.
• Conduction system: required for AV bundle/bundle-branch patterning and AV node maturation
  PMID:15289437; Tbx5-Nkx2-5-Id2 pathway specifies ventricular conduction system PMID:17604724.
• Adult atrial rhythm: Tbx5 -> Pitx2 incoherent feed-forward network; adult deletion causes AF
  PMID:27582060. Human TBX5 variants associated with AF and DCM [PMID:27035640; PMID:25963046].
• Overexpression inhibits cardiomyocyte proliferation (chick, partly non-cell-autonomous) PMID:11161571
  and cell growth of cultured cells PMID:12237100; proepicardial migration affected by both gain and
  loss PMID:15138308. These are dosage/overexpression readouts and treated as non-core.

Curation decisions summary

• Core MF: GO:0000981 (with GO:0000978 binding) and partner-TF binding GO:0061629.
• Core BP: heart development, embryonic forelimb morphogenesis; non-core: conduction-system,
  septation and atrial rhythm subterms.
• Generic protein binding: TF partners -> GO:0061629; TAZ/YAP1 -> GO:0001223; KAT2A/B -> GO:0035035;
  HuRI-only Y2H partners (ZMYND10, BAIAP2) removed.
• PMID:20299672 (review on epicardial growth-factor signalling): cached text does not mention TBX5;
  TAS rows from it treated cautiously.
• Module (cardiac_specification_network, tbox_tf annoton GO:0000981 / heart development / nucleus)
  is consistent with this review.