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Multiplexed measurement of variant abundance and activity reveals VKOR topology, active site and human variant impact

ABSTRACT: Multiplexed measurement of variant abundance and activity reveals VKOR topology, active site and human variant impact

PROVIDER: PRJNA630502 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11692700_1.fastq.gz	Fastqsanger.gz
	SRR11692700_2.fastq.gz	Fastqsanger.gz
	SRR11692701_1.fastq.gz	Fastqsanger.gz
	SRR11692701_2.fastq.gz	Fastqsanger.gz
	SRR11692702_1.fastq.gz	Fastqsanger.gz

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Multiplexed measurement of variant abundance and activity reveals VKOR topology, active site and human variant impact

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Multiplexed measurement of variant abundance and activity reveals VKOR topology, active site and human variant impact.

Project description:Vitamin K epoxide reductase (VKOR) drives the vitamin K cycle, activating vitamin K-dependent blood clotting factors. VKOR is also the target of the widely used anticoagulant drug, warfarin. Despite VKOR's pivotal role in coagulation, its structure and active site remain poorly understood. In addition, VKOR variants can cause vitamin K-dependent clotting factor deficiency or alter warfarin response. Here, we used multiplexed, sequencing-based assays to measure the effects of 2,695 VKOR missense variants on abundance and 697 variants on activity in cultured human cells. The large-scale functional data, along with an evolutionary coupling analysis, supports a four transmembrane domain topology, with variants in transmembrane domains exhibiting strongly deleterious effects on abundance and activity. Functionally constrained regions of the protein define the active site, and we find that, of four conserved cysteines putatively critical for function, only three are absolutely required. Finally, 25% of human VKOR missense variants show reduced abundance or activity, possibly conferring warfarin sensitivity or causing disease.

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Project description:Amino acid substitutions can perturb protein activity in multiple ways. Understanding their mechanistic basis may pinpoint how residues contribute to protein function. Here, we characterize the mechanisms of human glucokinase (GCK) variants, building on our previous comprehensive study on GCK variant activity. We assayed the abundance of 95\% GCK missense and nonsense variants, and found that 59\% of hypoactive variants have a decreased cellular abundance. By combining our abundance scores with predictions of protein thermodynamic stability, we identify residues important for GCK metabolic stability and conformational dynamics. These residues could be targeted to modulate GCK activity, and thereby affect glucose homeostasis.

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