Proteomics, Glycomics, and Glycoproteomics of Matrisome Molecules

Abstract

The most straightforward applications of proteomics database searching involve intracellular proteins. Although intracellular gene products number in the thousands, their well-defined post-translational modifications (PTMs) makes database searching practical. By contrast, cell surface and extracellular matrisome proteins pass through the secretory pathway where many become glycosylated, modulating their physicochemical properties, adhesive interactions, and diversifying their functions. Although matrisome proteins number only a few hundred, their high degree of complex glycosylation multiplies the number of theoretical proteoforms by orders of magnitude. Given that extracellular networks that mediate cell-cell and cell-pathogen interactions in physiology depend on glycosylation, it is important to characterize the proteomes, glycomes, and glycoproteomes of matrisome molecules that exist in a given biological context. In this review, we summarize proteomics approaches for characterizing matrisome molecules, with an emphasis on applications to brain diseases. We demonstrate the availability of methods that should greatly increase the availability of information on matrisome molecular structure associated with health and disease.

Keywords: Extracellular matrix; glycomics; glycoproteins; glycoproteomics; n-glycosylation.

Graphical abstract

Fig. 1.

Brain matrisome types include blood-brain barrier, interstitial matrix, and perineuronal nets. These structures are composed of matrisome molecules including hyaluronan, collagens, glycoproteins, and proteoglycans. Matrisome structure is spatially and temporally regulated, dynamic, and becomes altered during the pathogenesis of neuropsychiatric and neurodegenerative diseases.

Fig. 2.

Model for the structure of aggrecan, showing glycosylation with CS, HS, N-glycans, mucin-type O-GalNAc glycans, and O-Man glycans. The G1 and G2 domains contain link modules with homology to HAPLN proteins. The G3 domain has two epidermal growth factor (EGF)-like repeats; a C-type lectin domain, and a complement regulatory protein domain (CRP).

Fig. 3.

Higher energy collisional dissociation tandem mass spectrum of an aggrecan glycopeptide showing the presence of oxonium ions (green), peptide+saccharide ions (golden), and peptide backbone dissociation ions (red or blue) (140).