HICF2: LANCL3 A54V
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HIFC2 entry with custom annotation ported to Michelanglo.
TL;DR. The mutation is on a cytoplasmic loop that has diverged. One explanation is that it alters a protein binding site. However, other known mutations make this gene problematic.
Zinc binding. Homologue LANCL1 is 33% identical and has a structure. A54 is on a loop in the catalytic face of this membrane associated protein. It corresponds to G59 in LANCL1. This is the same face as the active site zinc, i.e. the zinc is cytosolic not vesicular/ER/ extracellular from what I can tell from the literature, but this may be wrong.
Role. LanC, the bacterial homologue, is part of a cyclic peptide synthesis pathway, and does a thiol-Michael addition. This is not an isoprenoid synthase, which catalyses a carbocation-alkene condensation. The former has a zinc as an ion, which stabilises the deprotonated thiol making it a strong nucleophile, while the latter has a magnesium that stabilises the pyrophosphate leaving group of the farnesyl-PP.
KO. In a paper (He et al., 2017) no gross abnormality was observed in triple LANCL1, LANCL2 and LANCL3 KO mice. However, it does have a pLI score of 0.5, so homozygous mutations are not tolerated in humans. But it is on the X chromosome (not pseudoautosomal), so I am not sure.
Model. An iTasser model was made, but in LANCL3 the loop with A54V is the part that differs strongly from LANCL3 —divergent selection? It is not a loop involved in EPS8 SH binding, so if it is a new binding site, it is for a different protein. The mutation may alter the loop orientation, but not cause destabilisation. I have correctly modelled the active site (GSH topology, GSH and Cys deprotonated and Zn-Sγ 2.35 Å), but it is too far away (14 Å away), so GSH conjugation is unaffected.
Minor observations. I am not sure how to tell which side is membrane side of this peripheral membrane protein, but I think it’s on the other side. Structurally the protein has a hole in the active site. Not mentioned in the LANCL1 paper.