Dataset Information

Differential interaction proteomics and phosphoproteomics of STK17B on an Oribtrap Astral, Nikiforov

ABSTRACT: LC-MS based DIA label free analysis of trubo-ID driven interaction study

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Erik Soderblom

LAB HEAD: Mikhail Nikiforov, PhD

PROVIDER: PXD068040 | Pride | 2025-09-05

REPOSITORIES: Pride

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Source:

			Action	DRS
	20240811_155325_10553_Zhibo_Phos_081124.sne	Other
	20240811_190927_10553_Zhibo_Open_081124.sne	Other
	ID116840_01_Open_SPD30_OA10034_10553_080824.raw	Raw
	ID116840_01_Phos_SPD30_OA10034_10553_080824.raw	Raw
	ID116841_01_Open_SPD30_OA10034_10553_080824.raw	Raw

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Project description:Liposomal amphotericin B is an important frontline drug for the treatment of visceral leishmaniasis, a neglected disease of poverty. The mechanism of action of amphotericin B (AmB) is thought to involve interaction with ergosterol and other ergostane sterols, resulting in disruption of the integrity and key functions of the plasma membrane. Emergence of clinically refractory isolates of L. donovani and L. infantum is an ongoing issue and knowledge of potential resistance mechanisms can help to alleviate this problem. Here we report the characterisation of four independently selected L. donovani clones that are resistant to AmB. Whole genome sequencing revealed that in three of the moderately resistant clones, resistance was due solely to the deletion of a gene encoding C24-sterol methyltransferase (SMT1). The fourth, hyper-resistant resistant clone (>60-fold) was found to have a 24 bp deletion in both alleles of a gene encoding a putative cytochrome P450 reductase (P450R1). Metabolic profiling indicated these parasites were virtually devoid of ergosterol (0.2% versus 18% of total sterols in wild-type) and had a marked accumulation of 14-methylfecosterol (75% versus 0.1% of total sterols in wild-type) and other 14-alpha methylcholestanes. These are substrates for sterol 14-alpha demethylase (CYP51) suggesting that this enzyme is a bona fide P450R specifically involved in electron transfer from NADPH to CYP51 during catalysis. Deletion of P450R1 in wild-type cells phenocopied the metabolic changes observed in our AmB hyper-resistant clone as well as in CYP51 nulls. Likewise, addition of a wild type P450R1 gene restored sterol profiles to wild type. Our studies indicate that P450R1 is essential for L. donovani amastigote viability, thus loss of this gene is unlikely to be a driver of clinical resistance. Nevertheless, investigating the mechanisms underpinning AmB resistance in these cells provided insights that refine our understanding of the L. donovani sterol biosynthetic pathway.

Dataset Information

Differential interaction proteomics and phosphoproteomics of STK17B on an Oribtrap Astral, Nikiforov

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