Proteomic insights into the extracellular matrix: a focus on proteoforms and their implications in health and disease

The extracellular matrix (ECM) is a highly organized and dynamic network of proteins and glycosaminoglycans that provides critical structural, mechanical, and biochemical support to cells. The functions of the ECM are directly influenced by the conformation of the proteins that compose it. ECM proteoforms, which can result from genetic, transcriptional, and/or post-translational modifications, adopt different conformations and, consequently, confer different structural properties and functionalities to the ECM in both physiological and pathological contexts.

In this review, we discuss how bottom-up proteomics has been applied to identify, map, and quantify post-translational modifications (e.g. additions of chemical groups, proteolytic cleavage, or cross-links) and ECM proteoforms arising from alternative splicing or genetic variants. We further illustrate how proteoform-level information can be leveraged to gain novel insights into ECM protein structure and ECM functions in health and disease.

In the Expert opinion section, we discuss remaining challenges and opportunities with an emphasis on the importance of devising experimental and computational methods tailored to account for the unique biochemical properties of ECM proteins with the goal of increasing sequence coverage and, hence, accurate ECM proteoform identification.