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Article
Nature Structural Biology  10, 250 - 255 (2003)
Published online: 3 March 2003; | doi:10.1038/nsb906

Structural insights into the U-box, a domain associated with multi-ubiquitination

Melanie D. Ohi1, 2, 3, Craig W. Vander Kooi3, 4, 5, Joshua A. Rosenberg1, 2, Walter J. Chazin4, 5, 6 & Kathleen L. Gould1, 2

1  Howard Hughes Medical Institute School of Medicine, Vanderbilt University, Nashville, Tennessee 37232, USA.

2  Department of Cell Biology, School of Medicine, Vanderbilt University, Nashville, Tennessee 37232, USA.

3  These authors contributed equally to this work.

4  Department of Biochemistry, Schools of Medicine and Arts & Science, Vanderbilt University, Nashville, Tennessee 37232, USA.

5  Center for Structural Biology, Schools of Medicine and Arts & Science, Vanderbilt University, Nashville, Tennessee 37232, USA.

6  Department of Physics, Schools of Medicine and Arts & Science, Vanderbilt University, Nashville, Tennessee 37232, USA.

Correspondence should be addressed to Walter J. Chazin walter.chazin@vanderbilt.edu or Kathleen L. Gould kathy.gould@mcmail.vanderbilt.edu
The structure of the U-box in the essential Saccharomyces cerevisiae pre-mRNA splicing factor Prp19p has been determined by NMR. The conserved zinc-binding sites supporting the cross-brace arrangement in RING-finger domains are replaced by hydrogen-bonding networks in the U-box. These hydrogen-bonding networks are necessary for the structural stabilization and activity of the U-box. A conservative Valright arrowIle point mutation in the Prp19p U-box domain leads to pre-mRNA splicing defects in vivo. NMR analysis of this mutant shows that the substitution disrupts structural integrity of the U-box domain. Furthermore, comparison of the Prp19p U-box domain with known RING−E2 complex structures demonstrates that both U-box and RING-fingers contain a conserved interaction surface. Mutagenesis of residues at this interface, while not perturbing the structure of the U-box, abrogates Prp19p function in vivo. These comparative structural and functional analyses imply that the U-box and its associated ubiquitin ligase activity are critical for Prp19p function in vivo.

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Spliceosomal Machinery
Nature Encyclopaedia of Life Sciences

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Nature Structural & Molecular Biology
ISSN: 1545-9993
EISSN: 1545-9985
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