Article
- The EMBO Journal (2004) 23, 1411 - 1421
- doi:10.1038/sj.emboj.7600114
Published online: 18 March 2004
Subject Categories:
Ubiquitin interactions of NZF zinc fingers
Steven L Alam1,5, Ji Sun2, Marielle Payne1, Brett D Welch1, B Kelly Blake1, Darrell R Davis1,3, Hemmo H Meyer4, Scott D Emr2 and Wesley I Sundquist1
- Department of Biochemistry, University of Utah, Salt Lake City, UT, USA
- Department of Cellular and Molecular Medicine, The Howard Hughes Medical Institute, University of California, San Diego School of Medicine, La Jolla, CA, USA
- Department of Medicinal Chemistry, University of Utah, Salt Lake City, UT, USA
- Swiss Federal Institute of Technology Zurich (ETH), Institute of Biochemistry, ETH Hoenggerberg HPM, Zurich, Switzerland
- Present address: School of Molecular Biosciences, Washington State University, PO Box 644660, Pullman, WA 99164-4660, USA
Correspondence to:
Steven L Alam, Department of Biochemistry, 3318 A Wintrobe Bldg, University of Utah, School of Medicine, 50 North Med. Drive, Salt Lake City, UT 84132-3201, USA. Tel.: +1 509 335 2765; Fax: +1 509 335 9688; E-mail: alam@wsu.edu
Wesley I Sundquist, Department of Biochemistry, 3318 A Wintrobe Bldg, University of Utah, School of Medicine, 50 North Med. Drive, Salt Lake City, UT 84132-3201, USA. Tel.: +1 801 585 5402; Fax: +1 801 581 7959; E-mail: wes@biochem.utah.edu
Received 17 November 2003; Accepted 15 January 2004
Abstract
Ubiquitin (Ub) functions in many different biological pathways, where it typically interacts with proteins that contain modular Ub recognition domains. One such recognition domain is the Npl4 zinc finger (NZF), a compact zinc-binding module found in many proteins that function in Ub-dependent processes. We now report the solution structure of the NZF domain from Npl4 in complex with Ub. The structure reveals that three key NZF residues (13TF14/M25) surrounding the zinc coordination site bind the hydrophobic 'Ile44' surface of Ub. Mutations in the 13TF14/M25 motif inhibit Ub binding, and naturally occurring NZF domains that lack the motif do not bind Ub. However, substitution of the 13TF14/M25 motif into the nonbinding NZF domain from RanBP2 creates Ub-binding activity, demonstrating the versatility of the NZF scaffold. Finally, NZF mutations that inhibit Ub binding by the NZF domain of Vps36/ESCRT-II also inhibit sorting of ubiquitylated proteins into the yeast vacuole. Thus, the NZF is a versatile protein recognition domain that is used to bind ubiquitylated proteins during vacuolar protein sorting, and probably many other biological processes.
Keywords:
- NMR spectroscopy,
- NZF domain,
- structure,
- ubiquitin,
- vacuolar protein sorting
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