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

Anabel-Lise Le Roux; Irrem-Laareb Mohammad; Borja Mateos; Miguel Arbesú; Margarida Gairí; Farman Ali Khan; João M C Teixeira; Miquel Pons

doi:10.1016/j.isci.2019.01.010

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

iScience. 2019 Feb 22:12:194-203. doi: 10.1016/j.isci.2019.01.010. Epub 2019 Jan 14.

Authors

Anabel-Lise Le Roux¹, Irrem-Laareb Mohammad¹, Borja Mateos¹, Miguel Arbesú¹, Margarida Gairí², Farman Ali Khan³, João M C Teixeira¹, Miquel Pons⁴

Affiliations

¹ BioNMR Laboratory, Inorganic and Organic Chemistry Department, Universitat de Barcelona, Baldiri Reixac, 10-12, 08028 Barcelona, Spain.
² NMR Facility, Scientific and Technological Centers, Universitat de Barcelona, Baldiri Reixac, 10-12, 08028 Barcelona, Spain.
³ BioNMR Laboratory, Inorganic and Organic Chemistry Department, Universitat de Barcelona, Baldiri Reixac, 10-12, 08028 Barcelona, Spain; Department of Biochemistry, Abdul Wali Khan University, Mardan 23200, Pakistan.
⁴ BioNMR Laboratory, Inorganic and Organic Chemistry Department, Universitat de Barcelona, Baldiri Reixac, 10-12, 08028 Barcelona, Spain. Electronic address: mpons@ub.edu.

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.

Keywords: Biophysics; Protein Structure Aspects; Structural Biology.