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Sci. Signal., 18 December 2012
Vol. 5, Issue 255, p. ra94
[DOI: 10.1126/scisignal.2003289]

RESEARCH ARTICLES

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

Dorothy Koveal1, Natasha Schuh-Nuhfer2, Daniel Ritt2, Rebecca Page1, Deborah K. Morrison2*, and Wolfgang Peti3,4*

1 Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02903, USA.
2 Laboratory of Cell and Developmental Signaling, SAIC-Frederick Inc., National Cancer Institute at Frederick, Frederick, MD 21702, USA.
3 Department of Molecular Pharmacology, Physiology and Biotechnology, Brown University, Providence, RI 02903, USA.
4 Department of Chemistry, Brown University, Providence, RI 02912, USA.

Abstract: Kinase suppressor of Ras-1 (KSR-1) is an essential scaffolding protein that coordinates the assembly of the mitogen-activated protein kinase (MAPK) module, consisting of the MAPK kinase kinase Raf, the MAPK kinase MEK (mitogen-activated or extracellular signal–regulated protein kinase kinase), and the MAPK ERK (extracellular signal–regulated kinase) to facilitate activation of MEK and thus ERK. Although KSR-1 is targeted to the cell membrane in part by its atypical C1 domain, which binds to phospholipids, other domains may be involved. We identified another domain in KSR-1 that we termed CC-SAM, which is composed of a coiled coil (CC) and a sterile α motif (SAM). The CC-SAM domain targeted KSR-1 to specific signaling sites at the plasma membrane in growth factor–treated cells, and it bound directly to various micelles and bicelles in vitro, indicating that the CC-SAM functioned as a membrane-binding module. By combining nuclear magnetic resonance spectroscopy and experiments in cultured cells, we found that membrane binding was mediated by helix α3 of the CC motif and that mutating residues in α3 abolished targeting of KSR-1 to the plasma membrane. Thus, in addition to the atypical C1 domain, the CC-SAM domain is required to target KSR-1 to the plasma membrane.

* To whom correspondence should be addressed. E-mail: morrisod{at}mail.nih.gov (D.K.M.); Wolfgang_Peti{at}brown.edu (W.P.)

Citation: D. Koveal, N. Schuh-Nuhfer, D. Ritt, R. Page, D. K. Morrison, W. Peti, A CC-SAM, for Coiled Coil–Sterile α Motif, Domain Targets the Scaffold KSR-1 to Specific Sites in the Plasma Membrane. Sci. Signal. 5, ra94 (2012).

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