The hanging heart: How KRAS lures its prey to the membrane

KRAS, known as the beating heart of cancer, drives around one in seven of all human cancers. Mutations in KRAS are most frequent in lung adenocarcinomas, colorectal cancers, and pancreatic cancers. KRAS is a small GTPase and the central switch in the MAPK signaling pathway. In cells, most signals are relayed and processed by proteins attached to or embedded in the membrane; KRAS signaling is no exception. However, obtaining insights into biochemical mechanisms at the membranes of cells has proven a significant technical challenge. Van et al. (1) utilize a suite of biophysical methods, capable of probing protein positioning at membranes, to elucidate how KRAS binds to the membrane of cells. They show that KRAS adopts a “hanging heart” conformation distal from the membrane, ready to recruit binding partners like a lure in fly-fishing dangling from the water’s surface, waiting to catch a fish. KRAS functions by cycling through two conformational states. Binding of the nucleotide guanosine diphosphate (GDP) stabilizes the signaling-incompetent state (KRASOFF), while the guanosine triphosphate (GTP) bound form (KRASON) is capable of binding downstream effectors (e.g., CRAF, PI3K, and RALGDS) and propagating signaling. Point mutations, most commonly at codons 12, 13, and 61, cause an increase in the levels of KRASON and lead to oncogenic forms of KRAS. KRAS is attached to the inner leaflet of the cell membrane in a bivalent manner via the … [↵][1]1To whom correspondence may be addressed. Email: darryl.mcconnell{at}boehringer-ingelheim.com. [1]: #xref-corresp-1-1