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Molecular and Cellular Biology, January 2009, p. 157-171, Vol. 29, No. 1
0270-7306/09/$08.00+0     doi:10.1128/MCB.01082-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Kinase-Inactivated ULK Proteins Inhibit Autophagy via Their Conserved C-Terminal Domains Using an Atg13-Independent Mechanism{triangledown}

Edmond Y. W. Chan,{dagger} Andrea Longatti,{ddagger} Nicole C. McKnight,{ddagger} and Sharon A. Tooze*

Secretory Pathways Laboratory, London Research Institute, Cancer Research UK, 44 Lincoln's Inn Fields, London WC2A 3PX, United Kingdom

Received 10 July 2008/ Returned for modification 11 August 2008/ Accepted 14 October 2008

The yeast Atg1 serine/threonine protein kinase and its mammalian homologs ULK1 and ULK2 play critical roles during the activation of autophagy. Previous studies have demonstrated that the conserved C-terminal domain (CTD) of ULK1 controls the regulatory function and localization of the protein. Here, we explored the role of kinase activity and intramolecular interactions to further understand ULK function. We demonstrate that the dominant-negative activity of kinase-dead mutants requires a 7-residue motif within the CTD. Our data lead to a model in which the functions of ULK1 and ULK2 are controlled by autophosphorylation and conformational changes involving exposure of the CTD. Additional mapping indicates that the CTD contains other distinct regions that direct membrane association and interaction with the putative human homologue of Atg13, which we have here characterized. Atg13 is required for autophagy and Atg9 trafficking during autophagy. However, Atg13 does not bind the 7-residue dominant-negative motif in the CTD of ULK proteins nor is the inhibitory activity of the CTDs rescued by Atg13 ectopic expression, suggesting that in mammalian cells, the CTD may interact with additional autophagy proteins.

* Corresponding author. Mailing address: Secretory Pathways Laboratory, London Research Institute, Cancer Research UK, 44 Lincoln's Inn Fields, London WC2A 3PX, United Kingdom. Phone: (44) 207 269 3122. Fax: (44) 207 269 3417. E-mail: sharon.tooze{at}cancer.org.uk

{triangledown} Published ahead of print on 20 October 2008.

{dagger} Present address: Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, United Kingdom.

{ddagger} These authors contributed equally to this work.

Molecular and Cellular Biology, January 2009, p. 157-171, Vol. 29, No. 1
0270-7306/09/$08.00+0     doi:10.1128/MCB.01082-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



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