Minimotifs dysfunction is pervasive in neurodegenerative disorders

: Changes in protein structure and function, alteration in protein-protein interaction, and significant difference in protein concentration inside the body could play an important role in indicating the pathological evidence of abnormalities before the development of clinical symptoms and act as a critical detection and diagnostic tool commonly known as biomarkers. Biomarkers play important roles in the diagnosis of various chronic diseases including cancer. Neurodegenerative disorders including Parkinson's, Alzheimer's, Huntington's, prion, and multiple sclerosis are well characterized by neuronal deterioration, resulting in precise modifications of neuronal proteins. Nowadays, the diagnosis of neurological disorders is based on protein or biomarker. These biomarkers may be found in the cerebrospinal fluid, blood, serum, plasma, saliva, or urine sample. Early diagnosis is urgently needed to prevent further circumstances. For early diagnosis, identifying the changes in novel protein levels and their functions under the disease conditions is necessary. These can be used as specific proteomic biomarkers for diseases, and they can be possibly identified using neuroproteomics. Neuroproteomics is an emerging tool to corroborate disease-associated protein profiles. It also gives an idea about how these proteins interact with other proteins and undergo post-translational modifications. Neuroproteomics is based on bioinformatics, which provides functional characteristics and advances in technology such as mass spectroscopy, and can help in the discovery of various disease-specific biomarkers. This review gives a complete idea about the types of biomarkers, sources of biomarkers, and techniques involved in the discovery of biomarkers for early diagnosis of neurodegenerative diseases.

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Systematic Assessment of Protein C-Termini Mutated in Human Disorders

FitzHugh

Schiller

2023

Biomolecules

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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.

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Minimotifs dysfunction is pervasive in neurodegenerative disorders

Cited by 3 publications

References 301 publications

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Systematic Assessment of Protein C-Termini Mutated in Human Disorders

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