Abstract
Heterogeneity is an inherent feature of the glycosylation process. Mammalian cells often produce a variety of glycan structures on separate molecules of the same protein, known as glycoforms. This heterogeneity is not random but is controlled by the organization of the glycosylation machinery in the Golgi cisternae. In this work, we use a computational model of the N-glycosylation process to probe how the organization of the glycosylation machinery into different cisternae drives N-glycan biosynthesis toward differing degrees of heterogeneity. Using this model, we demonstrate the N-glycosylation potential and limits of the mammalian Golgi apparatus, for example how the number of cisternae limits the goal of achieving near homogeneity for N-glycans. The production of specific glycoforms guided by this computational study could pave the way for “glycoform engineering,” which will find uses in the functional investigation of glycans, the modulation of glycan-mediated physiological functions, and in biotechnology.
Highlights
N-glycosylation is a process initiated in the endoplasmic reticulum (ER) but specific structural elements such as core fucosylation and branching (Figure 1A) are introduced later in the secretory pathway in the Golgi apparatus
It is not the aim of this work to describe in great detail the modeling methodology that has been used, a brief summary of the modeling methodology will give context and a greater understanding of the results of this work
In contrast to models of glycosylation based on ordinary differential equations (ODEs) (Hossler et al, 2007; Krambeck et al, 2009, 2017; Goey et al, 2018), several factors can be included in each parameter, reducing the need for excessive parameterization in our model
Summary
N-glycosylation is a process initiated in the endoplasmic reticulum (ER) but specific structural elements such as core fucosylation and branching (Figure 1A) are introduced later in the secretory pathway in the Golgi apparatus. In the absence of a “glycan template,” protein glycosylation is inherently heterogenous with a number of factors contributing to the final glycan structure. These variables include the protein structure (Hang et al, 2015; Suga et al, 2018), secretory protein load (JimenezMallebrera et al, 2009), Golgi transport mechanism (Hossler et al, 2007), enzyme protein levels, availability of monosaccharide-nucleotides, and the organization of glycosylation enzymes within the Golgi apparatus (Oka et al, 2004; Zolov and Lupashin, 2005; Fisher and Ungar, 2016). Following the initial trimming of mannoses by ManI, the number of possible N-glycan structures generated in the Golgi apparatus increases exponentially with each additional monosaccharide until the capping of antennae with sialic acid (Spahn et al, 2016)
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