The Functional Human C-Terminome

Abstract

All translated proteins end with a carboxylic acid commonly called the C-terminus. Many short functional sequences (minimotifs) are located on or immediately proximal to the C-terminus. However, information about the function of protein C-termini has not been consolidated into a single source. Here, we built a new “C-terminome” database and web system focused on human proteins. Approximately 3,600 C-termini in the human proteome have a minimotif with an established molecular function. To help evaluate the function of the remaining C-termini in the human proteome, we inferred minimotifs identified by experimentation in rodent cells, predicted minimotifs based upon consensus sequence matches, and predicted novel highly repetitive sequences in C-termini. Predictions can be ranked by enrichment scores or Gene Evolutionary Rate Profiling (GERP) scores, a measurement of evolutionary constraint. By searching for new anchored sequences on the last 10 amino acids of proteins in the human proteome with lengths between 3–10 residues and up to 5 degenerate positions in the consensus sequences, we have identified new consensus sequences that predict instances in the majority of human genes. All of this information is consolidated into a database that can be accessed through a C-terminome web system with search and browse functions for minimotifs and human proteins. A known consensus sequence-based predicted function is assigned to nearly half the proteins in the human proteome. Weblink: http://cterminome.bio-toolkit.com.

The carboxy-terminus, a key regulator of protein function

“…We have previously cataloged 3593 minimotifs in the human proteome that are anchored at the C-terminus and amalgamated in our C-terminome database/web-application (Sharma et al 2016). For these experimentally verified C-terminal minimotifs, 82% are PTMs, 18% bind protein domains, and less than 1% are for protein trafficking (Sharma et al 2016).…”

“…We have previously cataloged 3593 minimotifs in the human proteome that are anchored at the C-terminus and amalgamated in our C-terminome database/web-application (Sharma et al 2016). For these experimentally verified C-terminal minimotifs, 82% are PTMs, 18% bind protein domains, and less than 1% are for protein trafficking (Sharma et al 2016). For instance, the C-terminus of soluble proteins retained in the endoplasmic reticulum contains a KDEL > minimotif (letters are for the single letter amino acid code; “>” indicates the C-terminus of the proteins) (Cabrera et al 2003; Sharma et al 2016).…”

“…For these experimentally verified C-terminal minimotifs, 82% are PTMs, 18% bind protein domains, and less than 1% are for protein trafficking (Sharma et al 2016). For instance, the C-terminus of soluble proteins retained in the endoplasmic reticulum contains a KDEL > minimotif (letters are for the single letter amino acid code; “>” indicates the C-terminus of the proteins) (Cabrera et al 2003; Sharma et al 2016). Type II transmembrane proteins targeted to the plasma membrane often contains a CaaX > minimotif that enzymes recognize and prenylate the Cys thiol in the minimotif, “a” is an aliphatic amino acid, and “x” represents redundancy for any of the 20 amino acids (Sharma et al 2016; Wang and Casey 2016).…”

Minimotif Miner 4: a million peptide minimotifs and counting

“…The bias toward PTMs and instances likely reflects the increased application of high-throughput experimental approaches, primary affinity mass spectrometry. The new MnM 4 database contains ∼12 000 new C-terminal minimotifs on the last 10 amino acids of a protein, thus is a source of new information for the C-terminome minimotif database ( 33 ).…”

Minimotifs dysfunction is pervasive in neurodegenerative disorders

“…Minimotifs are important in protein trafficking to and from organelles and are relevant to several NDs [1,177,178]. Defects in endocytic and synaptic vesicle trafficking, Golgi trafficking, retrograde transport, and lysosomal autophagy are apparent in PD and AD [177,179,180].…”