Dataset Information

Polymorphic Histidine-rich Glycoprotein LC-MS/MS

ABSTRACT: Histidine-rich glycoprotein (HRG) HRG is a liver-produced protein circulating in human plasma serum at high concentrations of around 125 ug/mL. HRG belongs to the family of type-3 cystatins and has been implicated in a plethora of biological processes, albeit its precise function is still not well understood. Human HRG is a highly polymorphic protein, with at least 5 variants with minor allele frequencies (MAF) of more than 10%, variable in populations from different parts of the world. Considering these 5 mutations we can expect already 35 = 243 possible possibly genetic HRG variants in the population. Here, we purified HRG from serum of 44 individual donors and investigated by proteomics the occurrence of different allotypes, each being either homozygote or heterozygote for each of the 5 mutation sites. We observed that some mutational combinations in HRG were highly favored, while others were apparently missing, although they ought to be present based on the stochastic independent assembly of these 5 mutation sites. To further explore this behavior, we extracted data from the 1000 genome project (n ~ 2500 genomes) and assessed the frequency of different HRG mutants in this larger dataset, observing a prevailing agreement with our proteomics data. From all the proteogenomic data we conclude that the 5 different (frequent) mutations sites in HRG are not occurring independently, but some mutational variants at different sites are fully mutually exclusive, whereas other are highly intwined. Specific mutations also affect HRG abundance and its glycosylation. As the levels of HRG have been suggested as a protein biomarker in a variety of biological processes (e.g., aging, COVID-19 severity, severity of bacterial infections), we here conclude that the highly polymorphic nature of the protein needs to be considered in such evaluations, as these mutations affect HRG’s abundance, structure, post-translational modifications, and function.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Blood Serum

SUBMITTER: Yang Zou

LAB HEAD: Albert J.R. Heck

PROVIDER: PXD040914 | Pride | 2023-10-24

REPOSITORIES: Pride

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Dataset's files

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			Action	DRS
	20210927_EX3_UM7_Zou00006_SA_EXT00_F10_sHCD.raw	Raw
	20210927_EX3_UM7_Zou00006_SA_EXT00_F10_sHCD.raw.rar	Raw
	20210927_EX3_UM7_Zou00006_SA_EXT00_M2_HCD.raw	Raw
	20210927_EX3_UM7_Zou00006_SA_EXT00_M2_sHCD.raw	Raw
	20210927_EX3_UM7_Zou00006_SA_EXT00_M2_sHCD.raw.rar	Raw

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Publications

Proteogenomic Features of the Highly Polymorphic Histidine-rich Glycoprotein Arose Late in Evolution.

Zou Yang Y van Breukelen Bas B Pronker Matti M Reiding Karli K Heck Albert J R AJR

Molecular & cellular proteomics : MCP 20230525 7

Histidine-rich glycoprotein (HRG) is a liver-produced protein circulating in human serum at high concentrations of around 125 μg/ml. HRG belongs to the family of type-3 cystatins and has been implicated in a plethora of biological processes, albeit that its precise function is still not well understood. Human HRG is a highly polymorphic protein, with at least five variants with minor allele frequencies of more than 10%, variable in populations from different parts of the world. Considering these ...[more]

PMID: 37244517

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