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A Myristoyl-Binding Site in the SH3 Domain Modulates c-Src Membrane Anchoring.

ABSTRACT: The c-Src oncogene is anchored to the cytoplasmic membrane through its N-terminal myristoylated SH4 domain. This domain is part of an intramolecular fuzzy complex with the SH3 and Unique domains. Here we show that the N-terminal myristoyl group binds to the SH3 domain in the proximity of the RT loop, when Src is not anchored to a lipid membrane. Residues in the so-called Unique Lipid Binding Region modulate this interaction. In the presence of lipids, the myristoyl group is released from the SH3 domain and inserts into the lipid membrane. The fuzzy complex with the SH4 and Unique domains is retained in the membrane-bound form, placing the SH3 domain close to the membrane surface and restricting its orientation. The apparent affinity of myristoylated proteins containing the SH4, Unique, and SH3 domains is modulated by these intramolecular interactions, suggesting a mechanism linking c-Src activation and membrane anchoring.

SUBMITTER: Le Roux AL

PROVIDER: S-EPMC6354742 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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A Myristoyl-Binding Site in the SH3 Domain Modulates c-Src Membrane Anchoring.

Le Roux Anabel-Lise AL Mohammad Irrem-Laareb IL Mateos Borja B Arbesú Miguel M Gairí Margarida M Khan Farman Ali FA Teixeira João M C JMC Pons Miquel M

iScience 20190114

The c-Src oncogene is anchored to the cytoplasmic membrane through its N-terminal myristoylated SH4 domain. This domain is part of an intramolecular fuzzy complex with the SH3 and Unique domains. Here we show that the N-terminal myristoyl group binds to the SH3 domain in the proximity of the RT loop, when Src is not anchored to a lipid membrane. Residues in the so-called Unique Lipid Binding Region modulate this interaction. In the presence of lipids, the myristoyl group is released from the SH3 ...[more]

PMID: 30690395

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