Scratching the surface: Technologies for targeting the cell surfaceome

The development of methodologies that enable the study of the surface of a cell – the surfaceome – is pivotal to advancing the understanding of cellular differentiation, and through this will come the development of new, much-needed treatments.

The cell surface membrane – or plasma membrane (PM) – surrounds the cell providing necessary boundaries between the cytoplasm and the extracellular environment. This thin, semi-permeable membrane plays a vital role in protecting the integrity of the cell through selective movement of substances in and out. It also constitutes the base for the attachment of cytoskeleton and cell wall – for bacteria and plants – thereby providing and maintaining the shape of the cell. Moreover, PM allows cells to recognize one another and transmits signalling processes.

The building blocks of the cell membrane are lipids, proteins and their associated sugars. The composition and relative concentration of these molecules define the membrane function and vary among different organisms, cell types and cell states. Based on the fluid mosaic model introduced in 1972 by Singer and Nicolson, the PM is a mosaic of components – primarily phospholipids, cholesterol, proteins and associated carbohydrates – moving freely and fluidly in the plane of the membrane. Although it was thought that the distribution of components is uniform, current data suggest that the cell membrane is highly and tightly organised in heterogeneous microdomains: the maintenance of this heterogeneity is associated with a large energetic cost indicating its significance (1). In support of this hypothesis, perturbations to the lipid composition of the membrane that disrupt the proposed compartmentalisation drastically reduce the efficiency of signal transduction (1).

Introducing the surfaceome

Although lipids and glycans are key components of the PM, the focus of the present review is on the collection of proteins that resides at the cell surface or surfaceome. Surface proteins can be physically embedded in the lipid bilayer (integral), be anchored to the phospholipids or integral proteins at either side of the cell membrane (peripheral) or even associate to the membrane only under specific conditions. The surfaceome constitutes roughly 50% of the PM mass (2) and exhibits a wide variety of functions. These include transport, enzymatic activity, signal transduction, cell-cell interaction and attachment to the cytoskeleton or the extracellular matrix. Different classes of surface proteins carry out these tasks for example channel and carrier proteins, enzymes, receptors, cell recognition and cell adhesion proteins. Given the range of functions carried out by surface proteins, it is not surprising that roughly 30% of predicted open reading frames in a typical genome encode membrane and PM proteins (2).

The surfaceome content differs among cell types and changes during developmental and disease states. Therefore, it contains unique markers that can be used to distinguish cellular phenotypes and disease states. These properties along with the fact that cell surface proteins are readily available make the surfaceome a rich source of phenotypic, diagnostic, prognostic and therapeutic targets that can be used in a variety of fields including oncology, immunology and stem cell research.

Overall, the development of methodologies that enable the study of the surfaceome is pivotal to advance our understanding regarding cellular differentiation and development, host-pathogen interactions and metastatic processes, and will lead to the development of new treatments.

Do you want to read more? Download the white paper.

Download the white paper

The article was also published in the EBR Spring 2018