Systematic Assessment of Protein C-Termini Mutated in Human Disorders

Author:

FitzHugh Zachary T.12ORCID,Schiller Martin R.123ORCID

Affiliation:

1. Nevada Institute of Personalized Medicine, University of Nevada Las Vegas, 4505 S. Maryland Pkwy, Las Vegas, NV 89154, USA

2. School of Life Sciences, University of Nevada, 4505 S. Maryland Parkway, Las Vegas, NV 89154, USA

3. Heligenics Inc., 833 Las Vegas Blvd. North, Suite B, Las Vegas, NV 89101, USA

Abstract

All proteins have a carboxyl terminus, and we previously summarized eight mutations in binding and trafficking sequence determinants in the C-terminus that, when disrupted, cause human diseases. These sequence elements for binding and trafficking sites, as well as post-translational modifications (PTMs), are called minimotifs or short linear motifs. We wanted to determine how frequently mutations in minimotifs in the C-terminus cause disease. We searched specifically for PTMs because mutation of a modified amino acid almost always changes the chemistry of the side chain and can be interpreted as loss-of-function. We analyzed data from ClinVar for disease variants, Minimotif Miner and the C-terminome for PTMs, and RefSeq for protein sequences, yielding 20 such potential disease-causing variants. After additional screening, they include six with a previously reported PTM disruption mechanism and nine with new hypotheses for mutated minimotifs in C-termini that may cause disease. These mutations were generally for different genes, with four different PTM types and several different diseases. Our study helps to identify new molecular mechanisms for nine separate variants that cause disease, and this type of analysis could be extended as databases grow and to binding and trafficking motifs. We conclude that mutated motifs in C-termini are an infrequent cause of disease.

Funder

National Institutes of Health

Publisher

MDPI AG

Subject

Molecular Biology,Biochemistry

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