The carboxy-terminus, a key regulator of protein function

Abstract

All proteins end with a carboxyl terminus that has unique biophysical properties and is often disordered. Although there are examples of important C-termini functions, a more global role for the C-terminus is not yet established. In this review, we summarize research on C-termini, a unique region in proteins that cells exploit. Alternative splicing and proteolysis increase the diversity of proteins and peptides in cells with unique C-termini. The C-termini of proteins contain minimotifs, short peptides with an encoded function generally characterized as binding, posttranslational modifications, and trafficking. Many of these activities are specific to minimotifs on the C-terminus. Approximately 13% of C-termini in the human proteome have a known minimotif, and the majority, if not all of the remaining termini have conserved motifs inferring a function that remains to be discovered. C-termini, their predictions, and their functions are collated in the C-terminome, Proteus, and Terminus Oriented Protein Function INferred Database (TopFIND) database/web systems. Many C-termini are well conserved, and some have a known role in health and disease. We envision that this summary of C-termini will guide future investigation of their biochemical and physiological significance.

Keywords: C-terminal minimotifs; C-terminome; C-terminus; minimotifs; posttranslational modification; short linear motifs; trafficking.

Figure 1

Cellular processes creating a diverse C-terminal end. A protein-coding gene with three exons is transcribed into a pre-mRNA, alternative spliced, and each transcript is translated into a unique protein. Proteases cleave each protein and PTMs are attached creating new protein species.

Figure 2

Estimate of factors contributing to numbers of C-terminal ends in the human proteome. The human genome has approximately 22,000 protein-coding genes. Each gene produces five alternatively spliced transcripts, with approximately 110,000 transcripts encoding the same number of proteins. Assuming each protein is proteolyzed during its life producing eight proteins then there are 1.8 M proteins with c-termini. With approximately 10 PTMs per protein, there are 17.6 M unique possible proteins present in a cell assuming one modification per protein (Jensen 2004; de Klerk and ‘t Hoen 2015; Tress et al. 2017). If we consider all PTM permutations, there could be nearly a quadrillion unique protein molecules, far exceeding the estimated 10 billion proteins per cell.