Dataset Information

Bioinformatic identification of previously unrecognized amyloidogenic proteins.

ABSTRACT: Low-complexity domains (LCDs) of proteins have been shown to self-associate, and pathogenic mutations within these domains often drive the proteins into amyloid aggregation associated with disease. These domains may be especially susceptible to amyloidogenic mutations because they are commonly intrinsically disordered and function in self-association. The question therefore arises whether a search for pathogenic mutations in LCDs of the human proteome can lead to identification of other proteins associated with amyloid disease. Here, we take a computational approach to identify documented pathogenic mutations within LCDs that may favor amyloid formation. Using this approach, we identify numerous known amyloidogenic mutations, including several such mutations within proteins previously unidentified as amyloidogenic. Among the latter group, we focus on two mutations within the TRK-fused gene protein (TFG), known to play roles in protein secretion and innate immunity, which are associated with two different peripheral neuropathies. We show that both mutations increase the propensity of TFG to form amyloid fibrils. We therefore conclude that TFG is a novel amyloid protein and propose that the diseases associated with its mutant forms may be amyloidoses.

SUBMITTER: Rosenberg GM

PROVIDER: S-EPMC9108986 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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Publications

Bioinformatic identification of previously unrecognized amyloidogenic proteins.

Rosenberg Gregory M GM Murray Kevin A KA Salwinski Lukasz L Hughes Michael P MP Abskharon Romany R Eisenberg David S DS

The Journal of biological chemistry 20220409 5

Low-complexity domains (LCDs) of proteins have been shown to self-associate, and pathogenic mutations within these domains often drive the proteins into amyloid aggregation associated with disease. These domains may be especially susceptible to amyloidogenic mutations because they are commonly intrinsically disordered and function in self-association. The question therefore arises whether a search for pathogenic mutations in LCDs of the human proteome can lead to identification of other proteins ...[more]

PMID: 35405097

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Dataset Information

Bioinformatic identification of previously unrecognized amyloidogenic proteins.

Publications

Bioinformatic identification of previously unrecognized amyloidogenic proteins.

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