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Origin and Evolution of RAS Membrane Targeting
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Origin and Evolution of RAS Membrane Targeting
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Journal Article
Origin and Evolution of RAS Membrane Targeting
2023
Overview
KRAS
,
HRAS
and
NRAS
proto-oncogenes belong to a family of 40 highly homologous genes, which in turn are a subset of a superfamily of >160 genes encoding small GTPases. RAS proteins consist of a globular G-domain (aa1-166) and a 22-23 aa unstructured hypervariable region (HVR) that mediates membrane targeting. The evolutionary origins of the RAS isoforms, their HVRs and alternative splicing of the
KRAS
locus has not been explored. We found that
KRAS
is basal to the
RAS
proto-oncogene family and its duplication generated
HRAS
in the common ancestor of vertebrates. In a second round of duplication
HRAS
generated
NRAS and KRAS
generated an additional
RAS
gene we have designated
KRASBL
, absent in mammals and birds. KRAS4A arose through a duplication and insertion of the 4
th
exon of
NRAS
into the 3
rd
intron of
KRAS
. We found evolutionary conservation of a short polybasic region (PBR1) in HRAS, NRAS and KRAS4A, a second polybasic region (PBR2) in KRAS4A, two neutralized basic residues (NB) and a serine in KRAS4B and KRASBL, and a modification of the CaaX motif in vertebrates with farnesyl rather than geranylgeranyl polyisoprene lipids, suggesting that a less hydrophobic membrane anchor is critical to RAS protein function. The persistence of four RAS isoforms through >400 million years of evolution argues strongly for differential function.
