tailieunhanh - Báo cáo khoa học: Structural basis of p63a SAM domain mutants involved in AEC syndrome

The global regulator CymR represses the transcription of a large set of genes involved in cystine uptake and cysteine biosynthesis inBacillus subtilis andStaphylococcus aureus. This repressor belongs to the widespread and poorly characterized Rrf2 family of regulators. | IFEBS Journal Structural basis of p63a SAM domain mutants involved in AEC syndrome Aruna Sathyamurthy1 Stefan M. V. Freund2 Christopher M. Johnson2 Mark D. Allen2 and Mark Bycroft2 1 MRC Centre for Protein Engineering Cambridge UK 2 MRC Laboratory of Molecular Biology Cambridge UK Keywords 5-helix bundle AEC syndrome mutations p53 p63 p73 sterile alpha motif Correspondence M. D. Allen MRC Laboratory of Molecular Biology Hills Road Cambridge CB2 0QH UK Fax 44 0 1223 213556 Tel 44 0 1223 402409 E-mail mda201@ Received 9 July 2010 revised 11 April 2011 accepted 24 May 2011 doi 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. p63a contains a C-terminal sterile a 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 p63a SAM domain in patients suffering from ankyloblepharon-ectodermal dysplasia-clefting syndrome. Here we report the solution and high resolution crystal structures of the p63a 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. Introduction p63 is a member of the p53 tumour suppressor family that includes p73 however p63 does not function as a classical tumour suppressor and is rarely mutated in human cancers. Sequence homology and initial studies revealed that p63 could act as a DNA-sequence specific transcription factor for target genes that leads to apoptosis