STRUCTURAL BASIS OF P63A SAM DOMAIN MUTANTS INVOLVED IN AEC SYNDROME
[P63_HUMAN] Defects in TP63 are the cause of acro-dermato-ungual-lacrimal-tooth syndrome (ADULT syndrome) [MIM:103285]; a form of ectodermal dysplasia. Ectodermal dysplasias (EDs) constitute a heterogeneous group of developmental disorders affecting tissues of ectodermal origin. EDs are characterized by abnormal development of two or more ectodermal structures such as hair, teeth, nails and sweat glands, with or without any additional clinical sign. Each combination of clinical features represents a different type of ectodermal dysplasia. ADULT syndrome involves ectrodactyly, syndactyly, finger- and toenail dysplasia, hypoplastic breasts and nipples, intensive freckling, lacrimal duct atresia, frontal alopecia, primary hypodontia, and loss of permanent teeth. ADULT differs significantly from EEC3 syndrome by the absence of facial clefting. Defects in TP63 are the cause of ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) [MIM:106260]. AEC is an autosomal dominant condition characterized by congenital ectodermal dysplasia with coarse, wiry, sparse hair, dystrophic nails, slight hypohidrosis, scalp infections, ankyloblepharon filiform adnatum, maxillary hypoplasia, hypodontia and cleft lip/palate. Defects in TP63 are the cause of ectrodactyly-ectodermal dysplasia-cleft lip/palate syndrome type 3 (EEC3) [MIM:604292]. EEC3 is an autosomal dominant syndrome characterized by ectrodactyly of hands and feet, ectodermal dysplasia and facial clefting.    Defects in TP63 are the cause of split-hand/foot malformation type 4 (SHFM4) [MIM:605289]. Split-hand/split-foot malformation is a limb malformation involving the central rays of the autopod and presenting with syndactyly, median clefts of the hands and feet, and aplasia and/or hypoplasia of the phalanges, metacarpals, and metatarsals. There is restricted overlap between the mutational spectra of EEC3 and SHFM4.  Defects in TP63 are the cause of limb-mammary syndrome (LMS) [MIM:603543]. LMS is characterized by ectrodactyly, cleft palate and mammary-gland abnormalities. Note=Defects in TP63 are a cause of cervical, colon, head and neck, lung and ovarian cancers. Defects in TP63 are a cause of ectodermal dysplasia Rapp-Hodgkin type (EDRH) [MIM:129400]; also called Rapp-Hodgkin syndrome or anhidrotic ectodermal dysplasia with cleft lip/palate. Ectodermal dysplasia defines a heterogeneous group of disorders due to abnormal development of two or more ectodermal structures. EDRH is characterized by the combination of anhidrotic ectodermal dysplasia, cleft lip, and cleft palate. The clinical syndrome is comprised of a characteristic facies (narrow nose and small mouth), wiry, slow-growing, and uncombable hair, sparse eyelashes and eyebrows, obstructed lacrimal puncta/epiphora, bilateral stenosis of external auditory canals, microsomia, hypodontia, cone-shaped incisors, enamel hypoplasia, dystrophic nails, and cleft lip/cleft palate.    Defects in TP63 are the cause of non-syndromic orofacial cleft type 8 (OFC8) [MIM:129400]. Non-syndromic orofacial cleft is a common birth defect consisting of cleft lips with or without cleft palate. Cleft lips are associated with cleft palate in two-third of cases. A cleft lip can occur on one or both sides and range in severity from a simple notch in the upper lip to a complete opening in the lip extending into the floor of the nostril and involving the upper gum.
[P63_HUMAN] Acts as a sequence specific DNA binding transcriptional activator or repressor. The isoforms contain a varying set of transactivation and auto-regulating transactivation inhibiting domains thus showing an isoform specific activity. Isoform 2 activates RIPK4 transcription. May be required in conjunction with TP73/p73 for initiation of p53/TP53 dependent apoptosis in response to genotoxic insults and the presence of activated oncogenes. Involved in Notch signaling by probably inducing JAG1 and JAG2. Plays a role in the regulation of epithelial morphogenesis. The ratio of DeltaN-type and TA*-type isoforms may govern the maintenance of epithelial stem cell compartments and regulate the initiation of epithelial stratification from the undifferentiated embryonal ectoderm. Required for limb formation from the apical ectodermal ridge. Activates transcription of the p21 promoter.      
Publication Abstract from PubMed
p63 is a member of the p53 tumour suppressor family that includes p73. The p63 gene encodes a protein comprising an N-terminal transactivation domain, a DNA binding domain and an oligomerization domain, but varies in the organization of the C-terminus as a result of complex alternative splicing. p63alpha contains a C-terminal sterile alpha motif (SAM) domain that is thought to function as a protein-protein interaction domain. Several missense and heterozygous frame shift mutations, encoded within exon 13 and 14 of the p63 gene, have been identified in the p63alpha SAM domain in patients suffering from ankyloblepharon-ectodermal dysplasia-clefting syndrome. Here we report the solution and high resolution crystal structures of the p63alpha SAM domain and investigate the effect of several mutations (L553F/V, C562G/W, G569V, Q575L and I576T) on the stability of the domain. The possible effects of other mutations are also discussed. Database Coordinates are available in the Protein Data Bank database under the accession numbers 2Y9U and 2Y9T.
Structural basis of p63alpha SAM domain mutants involved in AEC syndrome.,Sathyamurthy A, Freund SM, Johnson CM, Allen MD, Bycroft M FEBS J. 2011 Aug;278(15):2680-8. doi: 10.1111/j.1742-4658.2011.08194.x., Epub 2011 Jun 20. PMID:21615690
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.