Investigation on the Oligomeric Status and Thermal Stability Properties of Pathological Mutations of KDSR in Progressive Symmetrical Erythematokeratosis
10.13865/j.cnki.cjbmb.2025.06.1217
- VernacularTitle:进行性对称性红斑角化症致病因子—KDSR若干病理突变的聚合状态及热稳定性质探究
- Author:
Jia-Cong SUN
1
;
Li WANG
1
;
Xue GONG
1
;
Zhen-Lu LI
1
;
Cheng CHEN
1
Author Information
1. 天津大学生命科学学院15教330室,天津 300072
- Publication Type:Journal Article
- Keywords:
progressive symmetric erythrokeratodermia(PSEK);
3-ketodihydrosphingosine reductase(KDSR);
conformational stability;
pathogenic mutation
- From:
Chinese Journal of Biochemistry and Molecular Biology
2025;41(8):1169-1178
- CountryChina
- Language:Chinese
-
Abstract:
Progressive symmetric erythrokeratodermia(PSEK)is a rare hereditary skin disease charac-terized by symmetrical erythema,hyperkeratosis and multiorgan lesions.Its clinical phenotypes are highly heterogeneous and may be accompanied by symptoms such as thrombocytopenia,which can be fatal in se-vere cases.The genotype-phenotype association mechanism of PSEK is extremely complex.Currently,it is known that mutations in multiple genes such as GJB3,KDSR,and KRT83 can cause the disease.A-mong them,3-ketodihydrosphingosine reductase(KDSR)has been found to harbor nearly 20 clinical mu-tations.These mutations interfere with the de novo ceramide synthesis pathway,disrupt the homeostasis of the skin barrier,and cause platelet production disorders and multi-organ lesions,making it a current research hotspot in the molecular mechanism of PSEK.The pathogenic mutations of KDSR are widely and uniformly distributed throughout the entire protein,rather than being limited to the traditionally recog-nized active center,suggesting that the impairment of the KDSR enzymatic activity is not the only cause of PSEK.In view of this,this study selected four typical mutants of KDSR(KDSRQG55-56R,KDSRn38C,KDSRY186F,KDSRG182S),and first used recombinant expression technology to prepare pure and homoge-neous mutant proteins.Subsequently,thermal stability experiments as well as oligomerization analysis were conducted on these four mutant proteins.The results showed that the Tm values of the four mutants were significantly lower than that of the wild type.Particularly,KDSRF138C and KDSRQG55-56R were nearly completely denatured at physiological temperature.This result was perfectly consistent with the further Rosetta energy analysis.In conclusion,this study took several pathological mutations of the PSEK patho-genic factor KDSR as the research object and discovered that the conformational stability of KDSR might be closely related to the occurrence of PSEK pathogenicity,indicating that the imbalance of conformation-al homeostasis is very likely to be one of the common contributing factors of many genetic diseases,inclu-ding PSEK.This provides a new theoretical basis and reference for explaining the molecular mechanism of genotype-phenotype heterogeneity in many genetic diseases.
