Fig. 7.

Targeting KSR-1 to the plasma membrane ruffles in activated cells requires both the CC-SAM and C1 domains. KSR translocates from the cytosol to the plasma membrane upon RTK activation. CC-SAM, together with the atypical C1 domain (CA3), localizes KSR-1 to B-Raf–rich microdomains in the plasma membrane. CC-SAM membrane binding is mediated by CC helix α3. Residues Ile⁷¹ and Leu⁷⁸ in helix α3 are buried at the interface between helix α2 and helix α3. In the membrane-bound form of the CC-SAM, a structural rearrangement occurs whereby helix α2 releases helix α3, exposing Ile⁷¹ and Leu⁷⁸, so that they can engage in membrane binding. Arg⁷², Lys⁷⁷, and Lys⁸⁰ are positioned such that they compensate for the negatively charged surface of the plasma membrane.