Article
- The EMBO Journal (2007) 26, 1963 - 1971
- doi:10.1038/sj.emboj.7601646
Published online: 15 March 2007
Subject Categories:
Structure of Sla1p homology domain 1 and interaction with the NPFxD endocytic internalization motif
Ravi K Mahadev1,a, Santiago M Di Pietro2,a, John M Olson2, Hai Lan Piao2, Gregory S Payne2 and Michael Overduin1
- CR-UK Institute for Cancer Studies, School of Medicine, University of Birmingham, Birmingham, UK
- Department of Biological Chemistry, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
Correspondence to:
Gregory S Payne, Department of Biological Chemistry, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA. Tel.: +1 310 206 3121; Fax: +1 310 206 5272; E-mail: gpayne@mednet.ucla.edu
Michael Overduin, CR-UK Institute for Cancer Studies, School of Medicine, University of Birmingham, Birmingham, B15 2TT, UK. Tel.: +44 121 414 3802; Fax: +44 121 414 4486; E-mail: m.overduin@bham.ac.uk
aThese authors contributed equally to this work
Received 12 October 2006; Accepted 13 February 2007
Abstract
Adaptor proteins play important endocytic roles including recognition of internalization signals in transmembrane cargo. Sla1p serves as the adaptor for uptake of transmembrane proteins containing the NPFxD internalization signal, and is essential for normal functioning of the actin cytoskeleton during endocytosis. The Sla1p homology domain 1 (SHD1) within Sla1p is responsible for recognition of the NPFxD signal. This study presents the NMR structure of the NPFxD-bound state of SHD1 and a model for the protein–ligand complex. The 
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structure of the protein reveals an SH3-like topology with a solvent-exposed hydrophobic ligand binding site. NMR chemical shift perturbations and effects of structure-based mutations on ligand binding in vitro define residues that are key for NPFxD binding. Mutations that abolish ligand recognition in vitro also abolish NPFxD-mediated receptor internalization in vivo. Thus, SHD1 is a novel functional domain based on SH3-like topology, which employs a unique binding site to recognize the NPFxD endocytic internalization signal. Its distant relationship with the SH3 fold endows this superfamily with a new role in endocytosis.
Keywords:
- endocytosis,
- NMR,
- NPFxD,
- Sla1p homology domain 1
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