Structures of Angptl3 and Angptl4, modulators of triglyceride levels and coronary artery disease

Abstract

Coronary artery disease is the most common cause of death globally and is linked to a number of risk factors including serum low density lipoprotein, high density lipoprotein, triglycerides and lipoprotein(a). Recently two proteins, angiopoietin-like protein 3 and 4, have emerged from genetic studies as being factors that significantly modulate plasma triglyceride levels and coronary artery disease. The exact function and mechanism of action of both proteins remains to be elucidated, however, mutations in these proteins results in up to 34% reduction in coronary artery disease and inhibition of function results in reduced plasma triglyceride levels. Here we report the crystal structures of the fibrinogen-like domains of both proteins. These structures offer new insights into the reported loss of function mutations, the mechanisms of action of the proteins and open up the possibility for the rational design of low molecular weight inhibitors for intervention in coronary artery disease.

A review of the multifunctionality of angiopoietin-like 4 in eye disease

“…This protein has some N- and O-glycosylation sites and was confirmed to be N-glycosylated at amino acid position 177 [ 8 ]. Ruddock and co-workers [ 9 ] provided the first evidence of the crystal structures of the FLDs of ANGPTL4 protein. The FLDs of ANGPTL4 form compact structures and is split into three subdomains A, B, and P. The N-terminal domain (subdomain A) is the most conserved amongst the FLD containing homologs and superimposes well in ANGPTL4, subdomain B is the largest subdomain amongst the three subdomains, the subdomain P varies the most amongst FLD containing proteins which functions as a site for ligand binding.…”

“…The FLDs of ANGPTL4 form compact structures and is split into three subdomains A, B, and P. The N-terminal domain (subdomain A) is the most conserved amongst the FLD containing homologs and superimposes well in ANGPTL4, subdomain B is the largest subdomain amongst the three subdomains, the subdomain P varies the most amongst FLD containing proteins which functions as a site for ligand binding. There are obviously differences in the structures of subdomain P between ANGPTL3 and ANGPTL4 indicating that while loss-of-function mutations, ANGPTL3 and ANGPTL4 act by different pathways [ 9 ].…”

Mapping the sites of the lipoprotein lipase (LPL)–angiopoietin-like protein 4 (ANGPTL4) interaction provides mechanistic insight into LPL inhibition

“…ANGPTL4 was originally thought to be an adipokine given its robust expression in adipocytes and hepatocytes, but it has since been reclassified with roles in angiogenesis, wound repair, kidney function, tumorigenesis, redox regulation, and energy homeostasis (29). Structurally, ANGPTL4 is composed of a coiled-coil N-terminal domain and a C-terminal fibrinogenlike domain that is selectively cleaved by proprotein convertases in certain tissues (30,31). Adipocytes primarily secrete fulllength ANGPTL4, and hepatocytes secrete the cleaved N-and C-terminal domains (29,32).…”

Identifying individual risk rare variants using protein structure guided local tests (POINT)

“…SVT and POINT-Burden identify variant G223; POINT additionally identifies E190 and Q331; REBET reports Subregion 1 (the most significant) and Subregions 2+3 as significant; these regions include all POINT-identified variants. Among the genotyped variants in ANGPTL4 with the ACCORD samples, the subdomain consisting of V308, G321, Q331 and R336 has been suggested to be a site for ligand binding (Biterova et al [49]). We see that both SVT and POINT yield a p-value near 0.05 for R336; POINT additinoally selects Q331, and REBET appears to capture the signal in Subregions 2+3.…”