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BIOLOGICAL SCIENCES / BIOCHEMISTRY
Structural insights into the p97-Ufd1-Npl4 complex

Valerie E. Pye^*, Fabienne Beuron^*,, Catherine A. Keetch, Ciaran McKeown^*, Carol V. Robinson, Hemmo H. Meyer, Xiaodong Zhang^*,¶, and Paul S. Freemont^*,¶

*Division of Molecular Biosciences, Faculty of Natural Sciences, Imperial College London, London SW7 2AZ, United Kingdom; Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, United Kingdom; and Institute of Biochemistry, Eidgenössiche Technische Hochschule Zurich, 8093 Zurich, Switzerland

Edited by Jeffrey Brodsky, University of Pittsburgh, Pittsburgh, PA, and accepted by the Editorial Board November 8, 2006 (received for review April 26, 2006)

p97/VCP (Cdc48 in yeast) is an essential and abundant member of the AAA+ family of ATPases and is involved in a number of diverse cellular pathways through interactions with different adaptor proteins. The two most characterized adaptors for p97 are p47 and the Ufd1 (ubiquitin fusion degradation 1)-Npl4 (nuclear protein localization 4) complex. p47 directs p97 to membrane fusion events and has been shown to be involved in protein degradation. The Ufd1-Npl4 complex directs p97 to an essential role in endoplasmic reticulum-associated degradation and an important role in mitotic spindle disassembly postmitosis. Here we describe the structural features of the Ufd1-Npl4 complex and its interaction with p97 with the aid of EM and other biophysical techniques. The Ufd1-Npl4 heterodimer has an elongated bilobed structure that is 80 x 30 Å in dimension. One Ufd1-Npl4 heterodimer is shown to interact with one p97 hexamer to form the p97-Ufd1-Npl4 complex. The Ufd1-Npl4 heterodimer emanates from one region on the periphery of the N-D1 plane of the p97 hexamer. Intriguingly, the p97-p47 and the p97-Ufd1-Npl4 complexes are significantly different in stoichiometry, symmetry, and quaternary arrangement, reflecting their specific actions and their ability to interact with additional cofactors that cooperate with p97 in diverse cellular pathways.

AAA ATPase | adaptor complex | ubiquitin | protein degradation | EM

Author contributions: V.E.P. and F.B. contributed equally to this work; V.E.P., F.B., C.V.R., H.H.M., X.Z., and P.S.F. designed research; V.E.P., F.B., C.A.K., and C.M. performed research; V.E.P., F.B., C.A.K., C.V.R., and H.H.M. contributed new reagents/analytic tools; V.E.P., F.B., C.A.K., C.V.R., X.Z., and P.S.F. analyzed data; and V.E.P., F.B., C.A.K., C.M., C.V.R., H.H.M., X.Z., and P.S.F. wrote the paper.

Present address: Section of Structural Biology, The Institute of Cancer Research, Chester Beatty Laboratories, 237 Fulham Road, London SW3 6JB, United Kingdom.

The authors declare no conflict of interest.

This article is a PNAS direct submission. J.B. is a guest editor invited by the Editorial Board.

This article contains supporting information online at www.pnas.org/cgi/content/full/0603408104/DC1.

^¶To whom correspondence may be addressed. E-mail: xiaodong.zhang{at}imperial.ac.uk or p.freemont{at}imperial.ac.uk

© 2007 by The National Academy of Sciences of the USA

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This article has been cited by other articles in HighWire Press-hosted journals:

				R. L. Isaacson, V. E. Pye, P. Simpson, H. H. Meyer, X. Zhang, P. S. Freemont, and S. Matthews Detailed Structural Insights into the p97-Npl4-Ufd1 Interface J. Biol. Chem., July 20, 2007; 282(29): 21361 - 21369. [Abstract] [Full Text] [PDF]

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