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J. Biol. Chem., Vol. 283, Issue 8, 5099-5109, February 22, 2008

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Solitary and Repetitive Binding Motifs for the AP2 Complex -Appendage in Amphiphysin and Other Accessory Proteins^*

Lene E. Olesen¹, Marijn G. J. Ford¹², Eva M. Schmid¹, Yvonne Vallis, M. Madan Babu, Peter H. Li³, Ian G. Mills⁴, Harvey T. McMahon⁵, and Gerrit J. K. Praefcke⁶

From the Laboratory of Molecular Biology, Medical Research Council, Neurobiology Division, Hills Road, Cambridge CB2 2QH, United Kingdom and the Center for Molecular Medicine Cologne, Institute for Genetics, Zülpicher Strasse 47, 50674 Cologne, Germany

Adaptor protein (AP) complexes bind to transmembrane proteins destined for internalization and to membrane lipids, so linking cargo to the accessory internalization machinery. This machinery interacts with the appendage domains of APs, which have platform and β-sandwich subdomains, forming the binding surfaces for interacting proteins. Proteins that interact with the subdomains do so via short motifs, usually found in regions of low structural complexity of the interacting proteins. So far, up to four motifs have been identified that bind to and partially compete for at least two sites on each of the appendage domains of the AP2 complex. Motifs in individual accessory proteins, their sequential arrangement into motif domains, and partial competition for binding sites on the appendage domains coordinate the formation of endocytic complexes in a temporal and spatial manner. In this work, we examine the dominant interaction sequence in amphiphysin, a synapse-enriched accessory protein, which generates membrane curvature and recruits the scission protein dynamin to the necks of coated pits, for the platform subdomain of the -appendage. The motif domain of amphiphysin1 contains one copy of each of a DX(F/W) and FXDXF motif. We find that the FXDXF motif is the main determinant for the high affinity interaction with the -adaptin appendage. We describe the optimal sequence of the FXDXF motif using thermodynamic and structural data and show how sequence variation controls the affinities of these motifs for the -appendage.

Received for publication, October 17, 2007 , and in revised form, November 2, 2007.

The atomic coordinates and structure factors (code 2vj0) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported by a fellowship from the Danish Research Academy (to L. E. O.), a research fellowship from Downing College, Cambridge, UK (to M. G. J. F.), a fellowship from the Austrian Academy of Science (to E. M. S.), and a Marie Curie Fellowship from European Union Contract HPMF-CT-2000-01086 (to G. J. K. P.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains a supplemental table.

¹ These authors contributed equally to this work.

² Present address: Section of Molecular and Cellular Biology, University of California, Davis, CA 95616.

³ Present address: Depts. of Ophthalmology and Physiology, University of California, San Francisco, 10 Koret Way, San Francisco, CA 94143-0730.

⁴ Present address: CRUK Uro-Oncology Research Group, Cambridge Cancer Research Institute, Robinson Way, Cambridge, CB2 0RE, UK.

⁵ To whom correspondence may be addressed. Tel.: 44-1223-402311; Fax: 44-1223-402310; E-mail: hmm{at}mrc-lmb.cam.ac.uk.

⁶ To whom correspondence may be addressed. Tel.: 49-221-470-1561; Fax: 49-221-470-6749; E-mail: gpraefck{at}uni-koeln.de.

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