6qsb
From Proteopedia
Crystal Structure of Arg470His mutant of Human Prolidase with Mn ions
Structural highlights
DiseasePEPD_HUMAN Defects in PEPD are a cause of prolidase deficiency (PD) [MIM:170100. Prolidase deficiency is an autosomal recessive disorder associated with iminodipeptiduria. The clinical phenotype includes skin ulcers, mental retardation, recurrent infections, and a characteristic facies. These features, however are incompletely penetrant and highly variable in both age of onset and severity. There is a tight linkage between the polymorphisms of prolidase and the myotonic dystrophy trait.[1] [2] [3] [4] FunctionPEPD_HUMAN Splits dipeptides with a prolyl or hydroxyprolyl residue in the C-terminal position. Plays an important role in collagen metabolism because the high level of iminoacids in collagen. Publication Abstract from PubMedProlidase Deficiency (PD) is an autosomal recessive rare disorder caused by loss or reduction of prolidase enzymatic activity due to variants in the PEPD gene. PD clinical features vary among affected individuals: skin ulcerations, recurrent infections, and developmental delay are common. In this study, we describe a 16-year-old boy with a mild PD phenotype comprising chronic eczema, recurrent infections and elevated IgE. Whole exome sequencing analysis revealed three PEPD variants: c.575T>C p.(Leu192Pro) inherited from the mother, and c.692_694del p.(Tyr231del) and c.1409G>A p.(Arg470His), both inherited from the father. The variant p.(Tyr231del) has been previously characterized by high-resolution X-ray structure analysis as altering protein dynamics/flexibility. In order to study the effects of the other two prolidase variants, we performed site directed mutagenesis purification and crystallization studies. A high-resolution X-ray structure could only be obtained for the p.(Arg470His) variant, which showed no significant structural differences in comparison to WT prolidase. On the other hand, the p.(Leu192Pro) variant led to significant protein destabilization. Hence, we conclude that the maternal p.(Leu192Pro) variant was likely causally associated with the proband s disease, together with the known pathogenic paternal variant p.(Tyr231del). Our results demonstrated the utility of exome sequencing to perform diagnosis in PD cases with mild phenotype. Structural analysis of new compound heterozygous variants in PEPD gene identified in a patient with Prolidase Deficiency diagnosed by exome sequencing.,Linhares ND, Wilk P, Wator E, Tostes MA, Weiss MS, Pena SDJ Genet Mol Biol. 2021 Apr 19;44(2):e20200393. doi: , 10.1590/1678-4685-GMB-2020-0393. eCollection 2021. PMID:33877262[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
| ||||||||||||||||||||
