Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2006 Mar 21;103(12):4675-80.
doi: 10.1073/pnas.0510403103. Epub 2006 Mar 13.

Structural basis for conformational plasticity of the Parkinson's disease-associated ubiquitin hydrolase UCH-L1

Chittaranjan Das  1 , Quyen Q Hoang, Cheryl A Kreinbring, Sarah J Luchansky, Robin K Meray, Soumya S Ray, Peter T Lansbury, Dagmar Ringe, Gregory A Petsko
Affiliations

Structural basis for conformational plasticity of the Parkinson's disease-associated ubiquitin hydrolase UCH-L1

Chittaranjan Das et al. Proc Natl Acad Sci U S A. .

Erratum in

  • Proc Natl Acad Sci U S A. 2006 Apr 25;103(17):6776

Abstract

The ubiquitin C-terminal hydrolase UCH-L1 (PGP9.5) comprises >1% of total brain protein but is almost absent from other tissues [Wilkinson, K. D., et al. (1989) Science 246, 670-673]. Mutations in the UCH-L1 gene have been reported to be linked to susceptibility to and protection from Parkinson's disease [Leroy, E., et al. (1998) Nature 395, 451-452; Maraganore, D. M., et al. (1999) Neurology 53, 1858-1860]. Abnormal overexpression of UCH-L1 has been shown to correlate with several forms of cancer [Hibi, K., et al. (1998) Cancer Res. 58, 5690-5694]. Because the amino acid sequence of UCH-L1 is similar to that of other ubiquitin C-terminal hydrolases, including the ubiquitously expressed UCH-L3, which appear to be unconnected to neurodegenerative disease, the structure of UCH-L1 and the effects of disease associated mutations on the structure and function are of considerable importance. We have determined the three-dimensional structure of human UCH-L1 at 2.4-A resolution by x-ray crystallography. The overall fold resembles that of other ubiquitin hydrolases, including UCH-L3, but there are a number of significant differences. In particular, the geometry of the catalytic residues in the active site of UCH-L1 is distorted in such a way that the hydrolytic activity would appear to be impossible without substrate induced conformational rearrangements.

PubMed Disclaimer

Conflict of interest statement

Conflict of interest statement: No conflicts declared.

Figures

Fig. 1.
Fig. 1.
Sequence alignment of UCH-L1 enzymes. Structure-based sequence alignment of UCH-L1 from different species is shown: HOM, Homo sapiens; MAC, Macaca fascicularis; SUS, Sus scrofa; EQU, Equus caballus; CAN, Canis familiaris; RAT, Rattus norvegicus; MUS, Mus musculus; TAE, Taeniopygia guttata; BUF, Bufo gargarizans; ACA, Acanthogobius flavimanus; ORE, Oreochromis niloticus; DAN, Danio rerio. The secondary structure elements of human UCH-L1 are indicated above that primary sequences, and conserved residues are highlighted (green, red, yellow, orange, and gray indicate conserved, hydrophobic, acidic, cyteine, polar, and glycine residues, respectively). Positions are identified as conserved if >80% of the residues are identical, or similar if hydrophobic in nature. δ, catalytic triad; ε, oxyanion hole; φ, H bonding with catalytic H161; γ, ubiquitin binding surface; η, P′ cleft; #, mutation site that reduced susceptibility to PD; ∗, mutation site that has been reported to cause familial PD; ∼, the loop spanning the active site. Mammalian sequences are boxed.
Fig. 2.
Fig. 2.
Structure of UCH-L1. (A) Ribbon representation of the structure of UCH-L1 dimer as presented in the crystal. One monomer is colored orange and the other is blue. N and C termini are labeled. (B) Stereo projection of a ribbon representation of UCH-L1 monomer. Helices are colored red, sheets are blue, and the rest are orange. Side-chain atoms of residues C90, I93, and S18 are shown as sticks. Secondary structures described in the text are labeled.
Fig. 3.
Fig. 3.
Molecular surface of UCH-L1. Conserved acidic side chains are colored red, basic side chains are colored blue, polar side chains are colored orange, and all nonconserved residues according to Fig. 1 are colored gray. B is related to A by a rotation of 50° about the y axis. D is related to C by a rotation of 90° about the x axis.
Fig. 4.
Fig. 4.
Structure of UCH-L1's active site. Backbone atoms are presented as semitransparent orange ribbons. Atoms of interest are presented as sticks and spheres. Oxygens, red; nitrogen, blue; sulfur, gold; chlorine, green. Distances between two atoms are presented with gray dashed lines. Electron density (contoured at 1.5σ) is shown as gray lines.
Fig. 5.
Fig. 5.
Structural comparison of UCH-L1 with its homologues. Superposition of UCH-L1 (orange) onto UCH-L3 (cyan), UCH-L3-UbVMe (magenta), and Yuh1-Ubal (green) is shown. B is related to A by 90° rotation about the x axis. (C) Atoms of selected side chains are shown as sticks. Oxygen, red; nitrogen, blue; sulfur, gold. (D) Backbone atoms of helix α6 and loop L8 are shown as sticks. Sulfur of residue C90 is shown as a sphere.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Hershko A., Ciechanover A., Varshavsky A. Nat. Med. 2000;6:1073–1081. - PubMed
    1. Amerik A. Y., Hochstrasser M. Biochim. Biophys. Acta. 2004;1695:189–207. - PubMed
    1. Chung C. H., Baek S. H. Biochem. Biophys. Res. Commun. 1999;266:633–640. - PubMed
    1. Wing S. S. Int. J. Biochem. Cell Biol. 2003;35:590–605. - PubMed
    1. Wilkinson K. D., Lee K. M., Deshpande S., Duerksen-Hughes P., Boss J. M., Pohl J. Science. 1989;246:670–673. - PubMed

Publication types

Substances