The hidden world of membrane microproteins

Abstract

Proteins are critical components of biological membranes and play key roles in many essential cellular processes. Membrane proteins are a structurally and functionally diverse family of proteins that have recently expanded to include a number of newly discovered tiny proteins called microproteins, or micropeptides. These microproteins are generated from small open reading frames, which produce protein products that are less than 100 amino acids in length. While not all microproteins are membrane proteins, this review will focus specifically on this subclass to highlight some of the important biological activities that have been ascribed to these molecules and to emphasize their promise as exciting new players in membrane biology.

Introduction

Biological membranes are dynamic structures that provide specialized permeability barriers for cells and subcellular organelles and are essential for life. Both prokaryotic and eukaryotic cells have a plasma membrane that forms an outer boundary of each cell and separates the interior of the cell from the external environment. Unlike prokaryotes, eukaryotic cells also contain internal membrane structures that define discrete organelles that perform specialized functions mediated by their unique microenvironments. Membranes are lipid bilayer structures that are primarily comprised of phospholipids, cholesterol and proteins held together by non-covalent forces. Membrane proteins account for roughly half the mass of most cellular membranes and they mediate critical cellular processes including ion transport, signal transduction, respiration, motility and cell-cell communication [1]. It has been estimated that one third of all protein-coding genes encode membrane proteins, and the importance of these proteins is highlighted by the fact that nearly half of all current therapeutic targets are membrane proteins [2,3].

Recently, the proteome has expanded to include a novel class of small proteins called microproteins, or micropeptides. These microproteins are translated from small open reading frames (sORFs) of less than 300 nucleotides in length to generate proteins that are 100 amino acids or smaller [4]. Due to their small size, many microprotein-coding genes have been unintentionally overlooked by standard gene annotation methods and have been incorrectly classified as noncoding RNAs. In recent years, a concentrated effort has been made to identify protein-coding sORFs, and innovative bioinformatic and technological advances have led to the discovery of hundreds of putative microproteins [[5], [6], [7], [8], [9], [10], [11]]. Interestingly, a high proportion of these microproteins are predicted to contain transmembrane α-helix motifs (Fig. 1), suggesting that microproteins may represent a rich source of uncharacterized membrane proteins [12,13]. To date, only a limited number of microproteins have been functionally characterized, and these proteins have been shown to play roles in a broad range of critical cellular functions including development, differentiation, stress signaling and metabolism (Fig. 2) [14,15]. The focus of this review will be to highlight the important roles that have been ascribed to membrane microproteins and to discuss the exciting potential these proteins hold as novel players in membrane biology.