A Genetic Approach to Mammalian Glycan Function

Abstract

The four essential building blocks of cells are proteins, nucleic acids, lipids, and glycans. Also referred to as carbohydrates, glycans are composed of saccharides that are typically linked to lipids and proteins in the secretory pathway. Glycans are highly abundant and diverse biopolymers, yet their functions have remained relatively obscure. This is changing with the advent of genetic reagents and techniques that in the past decade have uncovered many essential roles of specific glycan linkages in living organisms. Glycans appear to modulate biological processes in the development and function of multiple physiologic systems, in part by regulating protein-protein and cell-cell interactions. Moreover, dysregulation of glycan synthesis represents the etiology for a growing number of human genetic diseases. The study of glycans, known as glycobiology, has entered an era of renaissance that coincides with the acquisition of complete genome sequences for multiple organisms and an increased focus upon how posttranslational modifications to protein contribute to the complexity of events mediating normal and disease physiology. Glycan production and modification comprise an estimated 1% of genes in the mammalian genome. Many of these genes encode enzymes termed glycosyltransferases and glycosidases that reside in the Golgi apparatus where they play the major role in constructing the glycan repertoire that is found at the cell surface and among extracellular compartments. We present a review of the recently established functions of glycan structures in the context of mammalian genetic studies focused upon the mouse and human species. Nothing tends so much to the advancement of knowledge as the application of a new instrument. The native intellectual powers of men in different times are not so much the causes of the different success of their labours, as the peculiar nature of the means and artificial resources in their possession. T. Hager: Force of Nature (1)

GRASP55 Regulates Golgi Ribbon Formation

“…Diverse processes seem to depend on precise control of protein glycan "codes." Glycosyltransferase knockouts frequently cause strong developmental defects in mammals (Lowe and Marth, 2003;Angata et al, 2006), and altered protein glycosylation is frequently associated with malignant cancer (Sato and Furukawa, 2007).…”

N-acetylglucosaminyltransferase V inhibits the invasion of trophoblast cells by attenuating MMP2/9 activity in early human pregnancy

“…Glycosylation reactions are catalyzed by the glycosyltransferases, including N-acetylglucosaminyltransferase V (MGAT5), also known as GnT-V, which plays a regulatory role in the synthesis of complex N-glycans; this process is highly conserved in mammals [17,18]. It has been reported that an aberrant glycosylation induced by MGAT5 is associated with tumor malignant transformation, including tumor invasion and metastasis.…”

Altered Glycosylated PrP Proteins Can Have Different Neuronal Trafficking in Brain but Do Not Acquire Scrapie-like Properties

“…Processing of core glycans into the complex type is then achieved in the endoplasmic reticulum (ER) 4 and Golgi apparatus compartments (1). Protein-attached glycans have been shown to have a wide range of biological functions, most notably stabilization of protein structure and cellular trafficking (2).…”