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Novel polymorphisms of nuclear receptor SHP associated with functional and structural changes.

Authors
  • Zhou, Taofeng
  • Zhang, Yuxia
  • Macchiarulo, Antonio
  • Yang, Zhihong
  • Cellanetti, Marco
  • Coto, Eliecer
  • Xu, Pingyi
  • Pellicciari, Roberto
  • Wang, Li
Type
Published Article
Journal
Journal of Biological Chemistry
Publisher
American Society for Biochemistry and Molecular Biology
Publication Date
Aug 06, 2010
Volume
285
Issue
32
Pages
24871–24881
Identifiers
DOI: 10.1074/jbc.M110.133280
PMID: 20516075
Source
Medline
License
Unknown

Abstract

We identified three heterozygous nonsynonymous single nucleotide polymorphisms in the small heterodimer partner (SHP, NROB2) gene in normal subjects and CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy)-like patients, including two novel missense mutations (p.R38H, p.K170N) and one of the previously reported polymorphism (p.G171A). Four novel heterozygous mutations were also identified in the intron ((Intron)1265T-->A), 3'-untranslated region ((3'-UTR)101C-->G, (3'-UTR)186T-->C), and promoter ((Pro)-423C-->T) of the SHP gene. The exonic R38H and K170N mutants exhibited impaired nuclear translocation. K170N made SHP more susceptible to ubiquitination mediated degradation and blocked SHP acetylation, which displayed lost repressive activity on its interacting partners ERRgamma and HNF4alpha but not LRH-1. In contrast, G171A increased SHP mRNA and protein expression and maintained normal function. In general, the interaction of SHP mutants with LRH-1 and EID1 was enhanced. K170N also markedly impaired the recruitment of SHP, HNF4alpha, HDAC1, and HDAC3 to the apoCIII promoter. Molecular dynamics simulations of SHP showed that G171A stabilized the nuclear receptor boxes, whereas K170N promoted the conformational destabilization of all the structural elements of the receptor. This study suggests that genetic variations in SHP are common among human subjects and the Lys-170 residue plays a key role in controlling SHP ubiquitination and acetylation associated with SHP protein stability and repressive function.

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