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

Ekaterina Biterova,Heli I Alanen,Lloyd W Ruddock,Mirva Saaranen,Mariam Esmaeeli

doi:10.1038/s41598-018-25237-7

Ekaterina Biterova, Heli I Alanen + Show 3 more

Open Access

https://doi.org/10.1038/s41598-018-25237-7

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Journal: Scientific Reports	Publication Date: Apr 30, 2018
Citations: 38	License type: open-access

Affiliation: University of Oulu, University of Potsdam

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.

Highlights

Coronary artery disease (CAD) is the most common form of heart disease and is the most common cause of death globally, with CAD affecting 110 million people in 20151
Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have been developed to inhibit low density lipoprotein (LDL) uptake[14,15] and to reduce the incidence of CAD16. Parallel to this two other proteins have emerged – primarily from genetic studies – as being factors that significantly modulate plasma triglyceride levels and CAD. These proteins, human angiopoietin-like protein 3 (Angptl[3]; known as Ang5) and angiopoietin-like protein 4 (Angptl4) are, as the names suggest, related structurally to angiopoietins which are involved in angiogenesis via their interaction with the Tie[2] receptor[17]
For Angptl[3] loss of function mutations result in significantly lower levels of triglycerides, high density lipoprotein (HDL) cholesterol and low density lipoprotein (LDL) cholesterol[27,28,29,30,31], with carrier status associated with a 34% reduction in CAD29

Summary

Introduction

Coronary artery disease (CAD) is the most common form of heart disease and is the most common cause of death globally, with CAD affecting 110 million people in 20151. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have been developed to inhibit LDL uptake[14,15] and to reduce the incidence of CAD16 Parallel to this two other proteins have emerged – primarily from genetic studies – as being factors that significantly modulate plasma triglyceride levels and CAD. These proteins, human angiopoietin-like protein 3 (Angptl[3]; known as Ang5) and angiopoietin-like protein 4 (Angptl4) are, as the names suggest, related structurally to angiopoietins which are involved in angiogenesis via their interaction with the Tie[2] (tyrosine kinase with immunoglobulin and endothelial growth factor homology domain-2) receptor[17]. The exact function and mechanisms of action of both proteins remain to be elucidated, but both have been reported to interact with lipoprotein lipase[37,38]

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