期刊
ANNUAL REVIEW OF GENOMICS AND HUMAN GENETICS
卷 23, 期 -, 页码 475-498出版社
ANNUAL REVIEWS
DOI: 10.1146/annurev-genom-111221-103208
关键词
gain of function; dominant negative; protein interactions; ligand binding; protein complexes; activating mutations
Most disease-causing mutations occur in protein-coding regions of DNA, and these mutations can have non-loss-of-function effects via various molecular mechanisms, which can be understood by considering interactions with other molecules.
Most known disease-causing mutations occur in protein-coding regions of DNA. While some of these involve a loss of protein function (e.g., through premature stop codons or missense changes that destabilize protein folding), many act via alternative molecular mechanisms and have dominant-negative or gain-of-function effects. In nearly all cases, these non-loss-of-function mutations can be understood by considering interactions of the wild-type and mutant protein with other molecules, such as proteins, nucleic acids, or small ligands and substrates. Here, we review the diverse molecular mechanisms by which pathogenic mutations can have non-loss-of-function effects, including by disrupting interactions, increasing binding affinity, changing binding specificity, causing assembly-mediated dominant-negative and dominant-positive effects, creating novel interactions, and promoting aggregation and phase separation. We believe that increased awareness of these diverse molecular disease mechanisms will lead to improved diagnosis (and ultimately treatment) of human genetic disorders.
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