Structural basis of TBX5-DNA recognition: the T-box domain in its DNA-bound and -unbound form.

[holt-oram syndrome]

TBX 5 , a member of the T -box transcription factor family , plays an important role in heart and limb development . More than 60 single point or deletion mutations of human TBX 5 are associated with Holt-Oram syndrome that manifests itself as heart and limb malformations in 1 out of 100 ,000 live births . The majority of these mutations are located in the TBX 5 T -box domain . We solved the crystal structures of the human TBX 5 T -box domain in its DNA-unbound form and in complex with a natural DNA target site allowing for the first time the comparison between unbound and DNA-bound forms . Our analysis identifies a 3 (10 )-helix at the C-terminus of the T -box domain as an inducible recognition element , critically required for the interaction with DNA , as it only forms upon DNA binding and is unstructured in the DNA-unbound form . Using circular dichroism , we characterized the thermal stability of six TBX 5 mutants containing single point mutations in the T -box domain (M 74 V , G 8 0 R , W 121 G , G 169 R , T 22 3 M , and R 237 W ) and compared them with wild-type protein . Mutants G 8 0 R and W 121 G show drastically reduced thermal stability , while the other mutants only show a marginal stability decrease . For all TBX 5 mutants , binding affinities to specific and nonspecific DNA sequences were determined using isothermal titration calorimetry . All TBX 5 mutants show reduced binding affinities to a specific DNA target site , although to various degrees . Interestingly , all tested TBX 5 mutants differ in their ability to bind unspecific DNA , indicating that both sequence-specific and unspecific binding might contribute to the misregulation of target gene expression .

Diseases
Validation

Diseases presenting "first time" symptom

achondroplasia

acute rheumatic fever

adrenal incidentaloma

adrenomyeloneuropathy

alpha-thalassemia

aniridia

aromatase deficiency

canavan disease

carcinoma of the gallbladder

cholangiocarcinoma

classical phenylketonuria

congenital adrenal hyperplasia

congenital toxoplasmosis

cowden syndrome

cushing syndrome

cutaneous mastocytosis

dedifferentiated liposarcoma

dentin dysplasia

dentinogenesis imperfecta

dracunculiasis

dystrophic epidermolysis bullosa

epidermolysis bullosa simplex

erdheim-chester disease

erythropoietic protoporphyria

esophageal adenocarcinoma

esophageal carcinoma

esophageal squamous cell carcinoma

fabry disease

familial mediterranean fever

gm1 gangliosidosis

harlequin ichthyosis

heparin-induced thrombocytopenia

hirschsprung disease

hodgkin lymphoma, classical

holt-oram syndrome

hydrocephalus with stenosis of the aqueduct of sylvius

junctional epidermolysis bullosa

kabuki syndrome

kallmann syndrome

liposarcoma

locked-in syndrome

lymphangioleiomyomatosis

malignant atrophic papulosis

megacystis-microcolon-intestinal hypoperistalsis syndrome

monosomy 21

neuralgic amyotrophy

oculocutaneous albinism

oligodontia

omenn syndrome

oral submucous fibrosis

papillon-lefèvre syndrome

pendred syndrome

phenylketonuria

primary effusion lymphoma

primary hyperoxaluria type 1

severe combined immunodeficiency

sneddon syndrome

triple a syndrome

trochlear dysplasia

von hippel-lindau disease

waldenström macroglobulinemia

well-differentiated liposarcoma

werner syndrome

wiskott-aldrich syndrome

wolf-hirschhorn syndrome

x-linked adrenoleukodystrophy

zellweger syndrome

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