RT Journal Article
SR Electronic
T1 The Landscape of Mutations in Fumarate Hydratase
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 852392
DO 10.1101/852392
A1 David Shorthouse
A1 Michael W J Hall
A1 Benjamin A Hall
YR 2019
UL http://biorxiv.org/content/early/2019/11/23/852392.abstract
AB Fumarate Hydratase (FH) is an enzyme of the citric acid (TCA) cycle that is responsible for reversibly catalysing the conversion between fumarate and malate. FH loss and subsequent buildup of the oncometabolite fumarate causes hereditary leiomyomatosis and renal cell carcinoma.We sought to explore the mutational landscape of FH in silico, to predict the functional effects of many detected mutations, and categorise detected but un-characterised mutations in human populations. Using mutational energy predicting tools such as Rosetta and FoldX we can accurately predict mutations and mutational hotspots with high disruptive capability. Furthermore, through performing molecular dynamics simulations we show that hinge regions of the protein can be stabilized or destabilized by mutations, with new mechanistic implications of the consequences on the binding affinity of the enzyme for its substrates.We can additionally categorise a large majority of mutations and potential mutations into functional groups. This allows us to predict which detected mutations in the human population are likely to be loss-of-function, and therefore predispose patients to papillary renal carcinoma through considering only mutations to the protein binding site, hinges, and those that are buried deep within the protein. We additionally link mutation data to publicly available metabolomics data, and show that we can accurately predict which mutations in cancer cell lines are functionally relevant.