Research ArticleBiochemistry

A CC-SAM, for Coiled Coil–Sterile α Motif, Domain Targets the Scaffold KSR-1 to Specific Sites in the Plasma Membrane

Sci. Signal.  18 Dec 2012:
Vol. 5, Issue 255, pp. ra94
DOI: 10.1126/scisignal.2003289

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Another Helping Hand to the Membrane

Growth factor stimulation activates the mitogen-activated protein kinase module, in which Raf activates MEK, which in turn activates ERK. Kinase suppressor of Ras-1 (KSR-1) requires a phospholipid-binding atypical C1 domain to associate with the plasma membrane to promote assembly of this module. Koveal et al. identified a sterile α motif (SAM) adjacent to a coiled coil (CC) domain in KSR-1. Structural and biochemical analysis of just the CC and SAM regions showed that CC-SAM formed a single, structural module. CC-SAM bound directly to micelles and bicelles in vitro and was targeted to the plasma membrane in growth factor–treated cells. Structure-based point mutations in helix α3 of the CC motif prevented the binding of CC-SAM to micelles and bicelles. Full-length KSR-1 with these mutations did not localize to the plasma membrane or interact with B-Raf when expressed in growth factor–treated cells. Thus, KSR-1 requires the atypical C1 and CC-SAM domains to associate with the plasma membrane.