Lipoprotein Lipase: Structure, Function, and Genetic Variation

Figures

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  Figure 1. Summary of the catalytic functionality of lipoprotein lipase (LPL). (A) Monomeric LPL is bound to the luminal surface of endothelial cells by GPIHBP1 [1,21] in capillaries supplying skeletal muscle, cardiac muscle, or adipose tissues. Triglycerides (TGs) are transported throughout the body via TG-rich lipoproteins (TRLs), specifically chylomicrons and very-low-density lipoproteins, which carry TGs of dietary and hepatic origin, respectively. Apolipoproteins (apo) found on the surface of TRLs facilitate their interaction with membrane-bound LPL-GPIHBP1. TRL-bound apo A-V binds to the GPIHBP1 component, enhancing the association of the TRLs with LPL and the cell-surface features associated with LPL [31,32]. TRL-bound apo C-II interacts with multiple motifs in LPL itself, including the lid region of the LPL protein, inducing confirmational changes in LPL that enable the entry of TGs from the TRL into the LPL active site [29,30]. Membrane-bound LPL then hydrolyzes the TGs to 2 free fatty acid (FFA) molecules and one 2-monoacylglycerol molecule (2-MAG) [25]. The catalytic activity of LPL may be inhibited by other apolipoproteins on the surface of TRL, namely apo C-III, apo C-I, and/or…

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  Figure 2. Distribution of LPL gene pathogenic/likely pathogenic variants and variants of uncertain significance (VUS) by variant type. The grouped bar chart shows the number of each variant type we identified as pathogenic/likely pathogenic (red bars) or VUS (gold bars) according to the American College of Medical Genetics and Genomics (ACMG) guidelines. The X-axis indicates the variant type and the Y-axis indicates the number of variants identified in our compiled lists (See Supplementary Data for more details).

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  Figure 3. Distribution of pathogenic/likely pathogenic variants across all coding exons of the LPL gene. The bar chart shows the number of pathogenic/likely pathogenic variants (as identified according to the ACMG guidelines) found in each coding exon of the LPL gene. The X-axis indicates the exons and the Y-axis indicates the number of variants identified in our compiled list (See Supplementary Data for more details).

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  Figure 4. Protein map of reported LPL coding sequence variants encoded in exon 1. The number line indicates amino acid residue numbering in the primary structure of newly synthesized LPL peptide, with the specific numbers indicating the beginning and/or end of the functional domain they border. The black box indicates the residues forming the signal peptide. All variants are color-coded according to their ACMG pathogenicity classification: red indicates pathogenic or likely pathogenic and yellow orange indicates a variant of uncertain significance (VUS). Pathogenic/likely pathogenic variants are shown above the linear map, while VUS variants are shown below. For frameshift variants resulting in a premature stop codon, the notation ‘fs*(number)’ indicates that the frameshift variant results in stop codon at (number) of residues downstream of the variant site.

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  Figure 5. Protein map of reported LPL coding sequence variants encoded in exon 2. The number line indicates amino acid residue numbering in the primary structure of newly synthesized LPL peptide, with the specific numbers indicating the beginning and/or end of the functional domain they border. The light-green box indicates cysteine residues involved in the formation of intramolecular disulfide bonds. The pink box represents asparagine residues at which N-linked glycosylation has been found to occur. Yellow boxes represent residues involved in apo C-II binding. Blue boxes represent residues involved in ANGPTL4 binding. The brown box represents residues involved in the formation of an oxyanion hole in mature protein. Where residues have been found to be involved in multiple functions, multiple boxes are used to represent overlap. All variants are color-coded according to their ACMG pathogenicity classification: red indicates pathogenic or likely pathogenic, yellow orange indicates a variant of uncertain significance (VUS), and green indicates benign or likely benign. Pathogenic/likely pathogenic variants are shown above the linear map, while VUS and benign/likely benign variants are shown…

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  Figure 6. Protein map of reported LPL coding sequence variants encoded in exon 3. The number line indicates amino acid residue numbering in the primary structure of newly synthesized LPL peptide, with the specific numbers indicating the beginning and/or end of the functional domain they border. Yellow boxes represent residues involved in apo C-II binding. Blue boxes represent residues involved in ANGPTL4 binding. Where residues have been found to be involved in multiple functions, multiple boxes are used to represent overlap. All variants are color-coded according to their ACMG pathogenicity classification: red indicates pathogenic or likely pathogenic and yellow orange indicates a variant of uncertain significance (VUS). Pathogenic/likely pathogenic variants are shown above the linear map, while VUS variants are shown below. For frameshift variants resulting in a premature stop codon, the notation ‘fs*(number)’ indicates that the frameshift variant results in stop codon at (number) of residues downstream of the variant site.

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  Figure 7. Protein map of reported LPL coding sequence variants encoded in exon 4. The number line indicates amino acid residue numbering in the primary structure of newly synthesized LPL peptide, with the specific numbers indicating the beginning and/or end of the functional domain they border. Green boxes represent residues forming the catalytic triad of the LPL hydrolase domain. The brown box represents residues involved in the formation of an oxyanion hole in mature protein. All variants are color-coded according to their ACMG pathogenicity classification: red indicates pathogenic or likely pathogenic and yellow orange indicates a variant of uncertain significance (VUS). Pathogenic/likely pathogenic variants are shown above the linear map, while VUS variants are shown below. For frameshift variants resulting in a premature stop codon, the notation ‘fs*(number)’ indicates that the frameshift variant results in stop codon at (number) of residues downstream of the variant site.

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  Figure 8. Protein map of reported LPL coding sequence variants encoded in exon 5. The number line indicates amino acid residue numbering in the primary structure of newly synthesized LPL peptide, with the specific numbers indicating the beginning and/or end of the functional domain they border. Green boxes represent residues forming the catalytic triad of the LPL hydrolase domain. Purple boxes represent residues involved in the coordination of Ca2+ into the mature LPL protein. Yellow boxes represent residues involved in apo C-II binding. The light-green box indicates cysteine residues involved in the formation of intramolecular disulfide bonds. Red boxes represent residues forming the lid region involved in regulating substrate access to the active site of mature LPL. Blue boxes represent residues involved in ANGPTL4 binding. Where residues have been found to be involved in multiple functions, multiple boxes are used to represent overlap. All variants are color-coded according to their ACMG pathogenicity classification: red indicates pathogenic or likely pathogenic and yellow orange indicates a variant of uncertain significance (VUS). Pathogenic/likely pathogenic variants are shown above…

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  Figure 9. Protein map of reported LPL coding sequence variants encoded in exon 6. The number line indicates amino acid residue numbering in the primary structure of newly synthesized LPL peptide, with the specific numbers indicating the beginning and/or end of the functional domain they border. Red boxes represent residues forming the lid region involved in regulating substrate access to the active site of mature LPL. Yellow boxes represent residues involved in apo C-II binding. The light-green boxes indicate cysteine residues involved in the formation of intramolecular disulfide bonds. Green boxes represent residues forming the catalytic triad of the LPL hydrolase domain. All variants are color-coded according to their ACMG pathogenicity classification: red indicates pathogenic or likely pathogenic, yellow orange indicates a variant of uncertain significance (VUS), and green indicates benign or likely benign. Pathogenic/likely pathogenic variants are shown above the linear map, while VUS and benign/likely benign variants are shown below. Pathogenic/likely pathogenic variants are shown above the linear map, while VUS and benign/likely benign variants are shown below. For frameshift…

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  Figure 10. Protein map of reported LPL coding sequence variants encoded in exon 7. The number line indicates amino acid residue numbering in the primary structure of newly synthesized LPL peptide, with the specific numbers indicating the beginning and/or end of the functional domain they border. Orange boxes represent residues involved in interacting with finger 3 of the LU domain of GPIHBP1. All variants are color-coded according to their ACMG pathogenicity classification: red indicates pathogenic or likely pathogenic, yellow orange indicates a variant of uncertain significance (VUS), and green indicates benign or likely benign. Pathogenic/likely pathogenic variants are shown above the linear map, while VUS and benign/likely benign variants are shown below. For frameshift variants resulting in a premature stop codon, the notation ‘fs*(number)’ indicates that the frameshift variant results in stop codon at (number) of residues downstream of the variant site.

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  Figure 11. Protein map of reported LPL coding sequence variants encoded in exon 8. The number line indicates amino acid residue numbering in the primary structure of newly synthesized LPL peptide, with the specific numbers indicating the beginning and/or end of the functional domain they border. Turquoise boxes represent residues involved in the formation of a stabilizing hydrogen bond between LPL and GPIHBP1. The pink box represents asparagine residues at which N-linked glycosylation has been found to occur. Orange boxes represent residues involved in interacting with finger 3 of the LU domain of GPIHBP1. Light pink-purple boxes represent the Trp-rich lipid-binding domain. All variants are color-coded according to their ACMG pathogenicity classification: red indicates pathogenic or likely pathogenic, yellow orange indicates a variant of uncertain significance (VUS), and green indicates benign or likely benign. Pathogenic/likely pathogenic variants are shown above the linear map, while VUS and benign/likely benign variants are shown below. For frameshift variants resulting in a premature stop codon, the notation ‘fs*(number)’ indicates that the frameshift variant results in stop codon at…

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  Figure 12. Protein map of reported LPL coding sequence variants encoded in exon 9. The number line indicates amino acid residue numbering in the primary structure of newly synthesized LPL peptide, with the specific numbers indicating the beginning and/or end of the functional domain they border. Dark gray boxes represent residues involved in interacting with finger 1 of the LU domain of GPIHBP1. The light-green boxes indicate cysteine residues involved in the formation of intramolecular disulfide bonds. Yellow-green boxes represent residues involved in interacting with finger 2 of the LU domain of GPIHBP1. Orange boxes represent residues involved in interacting with finger 3 of the LU domain of GPIHBP1. Turquoise boxes represent residues involved in the formation of a stabilizing hydrogen bond between LPL and GPIHBP1. All variants are color-coded according to their ACMG pathogenicity classification: red indicates pathogenic or likely pathogenic, yellow orange indicates a variant of uncertain significance (VUS), and green indicates benign or likely benign. Pathogenic/likely pathogenic variants are shown above the linear map, while VUS and benign/likely benign variants are shown below. For…